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{{Infobox_gene}}
{{Infobox_gene}}
'''Pur-alpha''' is a [[protein]] that in humans is encoded by the ''PURA'' [[gene]]<ref name="ref1448097">{{cite journal | vauthors = Bergemann AD, Ma ZW, Johnson EM | title = Sequence of cDNA comprising the human pur gene and sequence-specific single-stranded-DNA-binding properties of the encoded protein | journal = Molecular and Cellular Biology | volume = 12 | issue = 12 | pages = 5673–82 | date = December 1992 | pmid = 1448097 | pmc = 360507 }}</ref> located at chromosome 5, band q31.<ref name="ref11417483">{{cite journal | vauthors = Lezon-Geyda K, Najfeld V, Johnson EM | title = Deletions of PURA, at 5q31, and PURB, at 7p13, in myelodysplastic syndrome and progression to acute myelogenous leukemia | journal = Leukemia | volume = 15 | issue = 6 | pages = 954–62 | date = June 2001 | pmid = 11417483 }}</ref><ref name="ref7606931">{{cite journal | vauthors = Ma ZW, Pejovic T, Najfeld V, Ward DC, Johnson EM | title = Localization of PURA, the gene encoding the sequence-specific single-stranded-DNA-binding protein Pur alpha, to chromosome band 5q31 | journal = Cytogenetics and Cell Genetics | volume = 71 | issue = 1 | pages = 64–7 | date = 1995 | pmid = 7606931 }}</ref>
'''Pur-alpha''' is a [[protein]] that in humans is encoded by the ''PURA'' [[gene]]<ref name="ref1448097">{{cite journal | vauthors = Bergemann AD, Ma ZW, Johnson EM | title = Sequence of cDNA comprising the human pur gene and sequence-specific single-stranded-DNA-binding properties of the encoded protein | journal = Molecular and Cellular Biology | volume = 12 | issue = 12 | pages = 5673–82 | date = December 1992 | pmid = 1448097 | pmc = 360507 | doi=10.1128/mcb.12.12.5673}}</ref> located at chromosome 5, band q31.<ref name="ref11417483">{{cite journal | vauthors = Lezon-Geyda K, Najfeld V, Johnson EM | title = Deletions of PURA, at 5q31, and PURB, at 7p13, in myelodysplastic syndrome and progression to acute myelogenous leukemia | journal = Leukemia | volume = 15 | issue = 6 | pages = 954–62 | date = June 2001 | pmid = 11417483 | doi=10.1038/sj.leu.2402108}}</ref><ref name="ref7606931">{{cite journal | vauthors = Ma ZW, Pejovic T, Najfeld V, Ward DC, Johnson EM | title = Localization of PURA, the gene encoding the sequence-specific single-stranded-DNA-binding protein Pur alpha, to chromosome band 5q31 | journal = Cytogenetics and Cell Genetics | volume = 71 | issue = 1 | pages = 64–7 | date = 1995 | pmid = 7606931 | doi=10.1159/000134065}}</ref>


Pur-alpha an ancient, multi-functional DNA- and RNA-binding protein.<ref name="ref1448097" /><ref name="ref7959008">{{cite journal | vauthors = Ma ZW, Bergemann AD, Johnson EM | title = Conservation in human and mouse Pur alpha of a motif common to several proteins involved in initiation of DNA replication | journal = Gene | volume = 149 | issue = 2 | pages = 311–4 | date = November 1994 | pmid = 7959008 }}</ref>  ''PURA'' is expressed in every human tissue. Human Pur-alpha is a protein of 322 amino acids. According to convention, ''PURA'', the gene, is written italicized in all upper case letters. Pur-alpha, the protein, is written with the first letter capitalized and can be found listed as Pur-alpha, Pur-α, Pura, Puralpha, Pur alpha and Pur1.
Pur-alpha an ancient, multi-functional DNA- and RNA-binding protein.<ref name="ref1448097" /><ref name="ref7959008">{{cite journal | vauthors = Ma ZW, Bergemann AD, Johnson EM | title = Conservation in human and mouse Pur alpha of a motif common to several proteins involved in initiation of DNA replication | journal = Gene | volume = 149 | issue = 2 | pages = 311–4 | date = November 1994 | pmid = 7959008 | doi=10.1016/0378-1119(94)90167-8}}</ref>  ''PURA'' is expressed in every human tissue. Human Pur-alpha is a protein of 322 amino acids. According to convention, ''PURA'', the gene, is written italicized in all upper case letters. Pur-alpha, the protein, is written with the first letter capitalized and can be found listed as Pur-alpha, Pur-α, Pura, Puralpha, Pur alpha and Pur1.


== Evolutionary conservation and function ==
== Evolutionary conservation and function ==


Pur-alpha was the first sequence-specific single-stranded DNA-binding protein to be discovered in higher organisms (GenBank M96684.1; GI:190749).<ref name="ref1448097" /> It binds to both single-stranded and double-stranded DNA, making contact with G residues in the purine-rich strand of its binding site. Cumulative data shows that Pur-alpha preferentially binds to the sequence (G<sub>2-4</sub>N<sub>1-3</sub>)<sub>n</sub>, where N is not G. N denotes a nucleotide, and n denotes the number of repeats of this small sequence. N may be repeated up to three times in this sequence.<ref name="ref1448097" /><ref name="ref15777841">{{cite journal | vauthors = Wortman MJ, Johnson EM, Bergemann AD | title = Mechanism of DNA binding and localized strand separation by Pur alpha and comparison with Pur family member, Pur beta | journal = Biochimica et Biophysica Acta | volume = 1743 | issue = 1-2 | pages = 64–78 | date = March 2005 | pmid = 15777841 | doi = 10.1016/j.bbamcr.2004.08.010 }}</ref> Following the identification of a Pur factor, which specifically bound a purine-rich sequence in the control region of the c-''MYC'' gene,<ref name="ref1545807">{{cite journal | vauthors = Bergemann AD, Johnson EM | title = The HeLa Pur factor binds single-stranded DNA at a specific element conserved in gene flanking regions and origins of DNA replication | journal = Molecular and Cellular Biology | volume = 12 | issue = 3 | pages = 1257–65 | date = March 1992 | pmid = 1545807 | pmc = 369558 }}</ref> the gene, ''PURA'', encoding the protein, Pur-alpha, was cloned and sequenced for both human<ref name="ref1448097" /> and mouse (GenBank U02098.1).<ref name="ref7959008" /> Pur-alpha belongs to the four-member Pur protein family, which also includes Pur-beta (GenBank AY039216.1; GI:14906267)<ref name="ref1448097" /> and two forms of Pur–gamma (Variant A, GenBank AF195513.2; Variant B, GenBank AY077841).<ref name="ref12034829">{{cite journal | vauthors = Liu H, Johnson EM | title = Distinct proteins encoded by alternative transcripts of the PURG gene, located contrapodal to WRN on chromosome 8, determined by differential termination/polyadenylation | journal = Nucleic Acids Research | volume = 30 | issue = 11 | pages = 2417–26 | date = June 2002 | pmid = 12034829 | pmc = 117198 }}</ref>
Pur-alpha was the first sequence-specific single-stranded DNA-binding protein to be discovered in higher organisms (GenBank M96684.1; GI:190749).<ref name="ref1448097" /> It binds to both single-stranded and double-stranded DNA, making contact with G residues in the purine-rich strand of its binding site. Cumulative data shows that Pur-alpha preferentially binds to the sequence (G<sub>2-4</sub>N<sub>1-3</sub>)<sub>n</sub>, where N is not G. N denotes a nucleotide, and n denotes the number of repeats of this small sequence. N may be repeated up to three times in this sequence.<ref name="ref1448097" /><ref name="ref15777841">{{cite journal | vauthors = Wortman MJ, Johnson EM, Bergemann AD | title = Mechanism of DNA binding and localized strand separation by Pur alpha and comparison with Pur family member, Pur beta | journal = Biochimica et Biophysica Acta | volume = 1743 | issue = 1–2 | pages = 64–78 | date = March 2005 | pmid = 15777841 | doi = 10.1016/j.bbamcr.2004.08.010 }}</ref> Following the identification of a Pur factor, which specifically bound a purine-rich sequence in the control region of the c-''MYC'' gene,<ref name="ref1545807">{{cite journal | vauthors = Bergemann AD, Johnson EM | title = The HeLa Pur factor binds single-stranded DNA at a specific element conserved in gene flanking regions and origins of DNA replication | journal = Molecular and Cellular Biology | volume = 12 | issue = 3 | pages = 1257–65 | date = March 1992 | pmid = 1545807 | pmc = 369558 | doi=10.1128/mcb.12.3.1257}}</ref> the gene, ''PURA'', encoding the protein, Pur-alpha, was cloned and sequenced for both human<ref name="ref1448097" /> and mouse (GenBank U02098.1).<ref name="ref7959008" /> Pur-alpha belongs to the four-member Pur protein family, which also includes Pur-beta (GenBank AY039216.1; GI:14906267)<ref name="ref1448097" /> and two forms of Pur–gamma (Variant A, GenBank AF195513.2; Variant B, GenBank AY077841).<ref name="ref12034829">{{cite journal | vauthors = Liu H, Johnson EM | title = Distinct proteins encoded by alternative transcripts of the PURG gene, located contrapodal to WRN on chromosome 8, determined by differential termination/polyadenylation | journal = Nucleic Acids Research | volume = 30 | issue = 11 | pages = 2417–26 | date = June 2002 | pmid = 12034829 | pmc = 117198 | doi=10.1093/nar/30.11.2417}}</ref>


Pur protein sequences from bacteria through humans contain an amino acid segment that is strongly conserved (see NCBI [https://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?uid=smart00712 smart00712]).<ref name="ref1448097" /><ref name="ref12894583">{{cite journal | vauthors = Johnson EM | title = The Pur protein family: clues to function from recent studies on cancer and AIDS | journal = Anticancer Research | volume = 23 | issue = 3A | pages = 2093–100 | date = 2003 | pmid = 12894583 }}</ref> Human Pur-alpha contains three repeats of this Pur domain and bacterial Pur-alpha contains one.<ref name="ref1448097" /><ref name="ref20976240">{{cite journal | vauthors = Graebsch A, Roche S, Kostrewa D, Söding J, Niessing D | title = Of bits and bugs--on the use of bioinformatics and a bacterial crystal structure to solve a eukaryotic repeat-protein structure | journal = PLoS One | volume = 5 | issue = 10 | pages = e13402 | date = October 2010 | pmid = 20976240 | pmc = 2954813 | doi = 10.1371/journal.pone.0013402 }}</ref> This evolutionary conservation means that the specific sequence of this domain is important for the survival of most species throughout the spectrum of living organisms. This essential nature of the Pur domain piques interest because the functions of Pur-alpha in lower organisms and in humans differ greatly. For example, Pur-alpha is essential for brain and blood cell development in mammals,<ref name="ref12972605">{{cite journal | vauthors = Khalili K, Del Valle L, Muralidharan V, Gault WJ, Darbinian N, Otte J, Meier E, Johnson EM, Daniel DC, Kinoshita Y, Amini S, Gordon J | title = Puralpha is essential for postnatal brain development and developmentally coupled cellular proliferation as revealed by genetic inactivation in the mouse | journal = Molecular and Cellular Biology | volume = 23 | issue = 19 | pages = 6857–75 | date = October 2003 | pmid = 12972605 | pmc = 193944 }}</ref> but bacteria have no brain and no blood. In humans Pur-alpha functions to activate transcription in the nucleus, to facilitate RNA transport in the cytoplasm and to regulate DNA replication in the cell cycle.<ref name="ref12894583" /> In certain functions Pur-alpha interacts with family member Pur-beta.<ref name="ref24446247">{{cite journal | vauthors = Hariharan S, Kelm RJ, Strauch AR | title = The Purα/Purβ single-strand DNA-binding proteins attenuate smooth-muscle actin gene transactivation in myofibroblasts | journal = Journal of Cellular Physiology | volume = 229 | issue = 9 | pages = 1256–71 | date = September 2014 | pmid = 24446247 | doi = 10.1002/jcp.24564 }}</ref><ref>{{cite journal | vauthors = Kelm RJ, Elder PK, Strauch AR, Getz MJ | title = Sequence of cDNAs encoding components of vascular actin single-stranded DNA-binding factor 2 establish identity to Puralpha and Purbeta | journal = The Journal of Biological Chemistry | volume = 272 | issue = 42 | pages = 26727–33 | date = October 1997 | pmid = 9334258 }}</ref> Several cell cycle regulatory functions may be mediated by Pur-alpha binding to Cyclin/Cdk protein kinases, which phosphorylate proteins regulating cell cycle transition points.<ref name="ref11329617">{{cite journal | vauthors = Barr SM, Johnson EM | title = Ras-induced colony formation and anchorage-independent growth inhibited by elevated expression of Puralpha in NIH3T3 cells | journal = Journal of Cellular Biochemistry | volume = 81 | issue = 4 | pages = 621–38 | date = 2001 | pmid = 11329617 }}</ref><ref name="ref15707957">{{cite journal | vauthors = Liu H, Barr SM, Chu C, Kohtz DS, Kinoshita Y, Johnson EM | title = Functional interaction of Puralpha with the Cdk2 moiety of cyclin A/Cdk2 | journal = Biochemical and Biophysical Research Communications | volume = 328 | issue = 4 | pages = 851–7 | date = March 2005 | pmid = 15707957 | doi = 10.1016/j.bbrc.2005.01.038 }}</ref> Requirements for Pur-alpha in all organisms are united by Pur-alpha’s ability to bind nucleic acids coupled to its ability to interact with regulatory and transport proteins.
Pur protein sequences from bacteria through humans contain an amino acid segment that is strongly conserved (see NCBI [https://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?uid=smart00712 smart00712]).<ref name="ref1448097" /><ref name="ref12894583">{{cite journal | vauthors = Johnson EM | title = The Pur protein family: clues to function from recent studies on cancer and AIDS | journal = Anticancer Research | volume = 23 | issue = 3A | pages = 2093–100 | date = 2003 | pmid = 12894583 }}</ref> Human Pur-alpha contains three repeats of this Pur domain and bacterial Pur-alpha contains one.<ref name="ref1448097" /><ref name="ref20976240">{{cite journal | vauthors = Graebsch A, Roche S, Kostrewa D, Söding J, Niessing D | title = Of bits and bugs--on the use of bioinformatics and a bacterial crystal structure to solve a eukaryotic repeat-protein structure | journal = PLOS ONE | volume = 5 | issue = 10 | pages = e13402 | date = October 2010 | pmid = 20976240 | pmc = 2954813 | doi = 10.1371/journal.pone.0013402 }}</ref> This evolutionary conservation means that the specific sequence of this domain is important for the survival of most species throughout the spectrum of living organisms. This essential nature of the Pur domain piques interest because the functions of Pur-alpha in lower organisms and in humans differ greatly. For example, Pur-alpha is essential for brain and blood cell development in mammals,<ref name="ref12972605">{{cite journal | vauthors = Khalili K, Del Valle L, Muralidharan V, Gault WJ, Darbinian N, Otte J, Meier E, Johnson EM, Daniel DC, Kinoshita Y, Amini S, Gordon J | title = Puralpha is essential for postnatal brain development and developmentally coupled cellular proliferation as revealed by genetic inactivation in the mouse | journal = Molecular and Cellular Biology | volume = 23 | issue = 19 | pages = 6857–75 | date = October 2003 | pmid = 12972605 | pmc = 193944 | doi=10.1128/mcb.23.19.6857-6875.2003}}</ref> but bacteria have no brain and no blood. In humans Pur-alpha functions to activate transcription in the nucleus, to facilitate RNA transport in the cytoplasm and to regulate DNA replication in the cell cycle.<ref name="ref12894583" /> In certain functions Pur-alpha interacts with family member Pur-beta.<ref name="ref24446247">{{cite journal | vauthors = Hariharan S, Kelm RJ, Strauch AR | title = The Purα/Purβ single-strand DNA-binding proteins attenuate smooth-muscle actin gene transactivation in myofibroblasts | journal = Journal of Cellular Physiology | volume = 229 | issue = 9 | pages = 1256–71 | date = September 2014 | pmid = 24446247 | doi = 10.1002/jcp.24564 }}</ref><ref>{{cite journal | vauthors = Kelm RJ, Elder PK, Strauch AR, Getz MJ | title = Sequence of cDNAs encoding components of vascular actin single-stranded DNA-binding factor 2 establish identity to Puralpha and Purbeta | journal = The Journal of Biological Chemistry | volume = 272 | issue = 42 | pages = 26727–33 | date = October 1997 | pmid = 9334258 | doi=10.1074/jbc.272.42.26727}}</ref> Several cell cycle regulatory functions may be mediated by Pur-alpha binding to Cyclin/Cdk protein kinases, which phosphorylate proteins regulating cell cycle transition points.<ref name="ref11329617">{{cite journal | vauthors = Barr SM, Johnson EM | title = Ras-induced colony formation and anchorage-independent growth inhibited by elevated expression of Puralpha in NIH3T3 cells | journal = Journal of Cellular Biochemistry | volume = 81 | issue = 4 | pages = 621–38 | date = 2001 | pmid = 11329617 | doi=10.1002/jcb.1099}}</ref><ref name="ref15707957">{{cite journal | vauthors = Liu H, Barr SM, Chu C, Kohtz DS, Kinoshita Y, Johnson EM | title = Functional interaction of Puralpha with the Cdk2 moiety of cyclin A/Cdk2 | journal = Biochemical and Biophysical Research Communications | volume = 328 | issue = 4 | pages = 851–7 | date = March 2005 | pmid = 15707957 | doi = 10.1016/j.bbrc.2005.01.038 }}</ref> Requirements for Pur-alpha in all organisms are united by Pur-alpha’s ability to bind nucleic acids coupled to its ability to interact with regulatory and transport proteins.


==Relevance in human diseases==
==Relevance in human diseases==
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=== Genetic perturbation in leukemia and anti-proliferative effect ===
=== Genetic perturbation in leukemia and anti-proliferative effect ===


''PURA'', located at chromosome 5 band q31, is frequently deleted in myelodysplastic syndrome (MDS),<ref>{{cite web|last1=Reference|first1=Genetics Home|title=PURA gene|url=https://ghr.nlm.nih.gov/gene/PURA|website=Genetics Home Reference|language=en}}</ref> a disorder of white blood cells, that may progress to acute myelogenous leukemia (AML).<ref name="ref11417483" /> Loss of one copy of chromosome 7 is also frequent in MDS. ''PURB'', the gene encoding Pur-beta, is located at 7p13. A visual fluorescence analysis of chromosomes from MDS patients shows that deletions of ''PURA'' at 5q31 are more strongly linked to progression of MDS to AML when combined with deletions of the ''PURB'' gene, including complete loss of chromosome 7.<ref name="ref11417483" /> All of the ''PURA'' deletions noted, involve only one of the two paired, parentally-derived chromosomes. The implication is that Pur-alpha and -beta are each codominantly expressed, and that haploid levels are insufficient for a protective effect against cancer. All known ''PURA'' deletions in people occur in only one of the two copies of chromosome 5.<ref>{{cite journal|last1=Hirai|first1=H|title=Molecular mechanisms of myelodysplastic syndrome.|journal=Japanese journal of clinical oncology|date=April 2003|volume=33|issue=4|pages=153–60|pmid=12810828}}</ref>
''PURA'', located at chromosome 5 band q31, is frequently deleted in myelodysplastic syndrome (MDS),<ref>{{cite web|last1=Reference|first1=Genetics Home|title=PURA gene|url=https://ghr.nlm.nih.gov/gene/PURA|website=Genetics Home Reference|language=en}}</ref> a disorder of white blood cells, that may progress to acute myelogenous leukemia (AML).<ref name="ref11417483" /> Loss of one copy of chromosome 7 is also frequent in MDS. ''PURB'', the gene encoding Pur-beta, is located at 7p13. A visual fluorescence analysis of chromosomes from MDS patients shows that deletions of ''PURA'' at 5q31 are more strongly linked to progression of MDS to AML when combined with deletions of the ''PURB'' gene, including complete loss of chromosome 7.<ref name="ref11417483" /> All of the ''PURA'' deletions noted, involve only one of the two paired, parentally-derived chromosomes. The implication is that Pur-alpha and -beta are each codominantly expressed, and that haploid levels are insufficient for a protective effect against cancer. All known ''PURA'' deletions in people occur in only one of the two copies of chromosome 5.<ref>{{cite journal|last1=Hirai|first1=H|title=Molecular mechanisms of myelodysplastic syndrome.|journal=Japanese journal of clinical oncology|date=April 2003|volume=33|issue=4|pages=153–60|pmid=12810828|doi=10.1093/jjco/hyg037}}</ref>


Inducing increased levels of Pur-alpha in several different cultured cancer cell lines blocks cell proliferation. It also blocks anchorage-independent colony formation, a hallmark of cancer.<ref name="ref11329617" /><ref name="ref11748591">{{cite journal | vauthors = Darbinian N, Gallia GL, King J, Del Valle L, Johnson EM, Khalili K | title = Growth inhibition of glioblastoma cells by human Pur(alpha) | journal = Journal of Cellular Physiology | volume = 189 | issue = 3 | pages = 334–40 | date = December 2001 | pmid = 11748591 | doi = 10.1002/jcp.10029 }}</ref> This is true whether Pur-alpha is microinjected or expressed after introducing a cloned ''PURA'' cDNA into cells.<ref name="ref10435638">{{cite journal | vauthors = Stacey DW, Hitomi M, Kanovsky M, Gan L, Johnson EM | title = Cell cycle arrest and morphological alterations following microinjection of NIH3T3 cells with Pur alpha | journal = Oncogene | volume = 18 | issue = 29 | pages = 4254–61 | date = July 1999 | pmid = 10435638 | doi = 10.1038/sj.onc.1202795 }}</ref> The Pur-alpha inhibition of cancer cell proliferation occurs at specific points in the cell division cycle, primarily at checkpoints for transition to DNA replication or mitosis.<ref name="ref10435638" /> These cell cycle effects are consistent with an interaction between Pur-alpha and CDK, cell cycle-dependent protein kinases.<ref name="ref11329617" /> They are also consistent with documented interaction between Pur-alpha and the tumor suppressor protein, Rb.<ref name="ref7592647">{{cite journal | vauthors = Johnson EM, Chen PL, Krachmarov CP, Barr SM, Kanovsky M, Ma ZW, Lee WH | title = Association of human Pur alpha with the retinoblastoma protein, Rb, regulates binding to the single-stranded DNA Pur alpha recognition element | journal = The Journal of Biological Chemistry | volume = 270 | issue = 41 | pages = 24352–60 | date = October 1995 | pmid = 7592647 }}</ref>
Inducing increased levels of Pur-alpha in several different cultured cancer cell lines blocks cell proliferation. It also blocks anchorage-independent colony formation, a hallmark of cancer.<ref name="ref11329617" /><ref name="ref11748591">{{cite journal | vauthors = Darbinian N, Gallia GL, King J, Del Valle L, Johnson EM, Khalili K | title = Growth inhibition of glioblastoma cells by human Pur(alpha) | journal = Journal of Cellular Physiology | volume = 189 | issue = 3 | pages = 334–40 | date = December 2001 | pmid = 11748591 | doi = 10.1002/jcp.10029 }}</ref> This is true whether Pur-alpha is microinjected or expressed after introducing a cloned ''PURA'' cDNA into cells.<ref name="ref10435638">{{cite journal | vauthors = Stacey DW, Hitomi M, Kanovsky M, Gan L, Johnson EM | title = Cell cycle arrest and morphological alterations following microinjection of NIH3T3 cells with Pur alpha | journal = Oncogene | volume = 18 | issue = 29 | pages = 4254–61 | date = July 1999 | pmid = 10435638 | doi = 10.1038/sj.onc.1202795 }}</ref> The Pur-alpha inhibition of cancer cell proliferation occurs at specific points in the cell division cycle, primarily at checkpoints for transition to DNA replication or mitosis.<ref name="ref10435638" /> These cell cycle effects are consistent with an interaction between Pur-alpha and CDK, cell cycle-dependent protein kinases.<ref name="ref11329617" /> They are also consistent with documented interaction between Pur-alpha and the tumor suppressor protein, Rb.<ref name="ref7592647">{{cite journal | vauthors = Johnson EM, Chen PL, Krachmarov CP, Barr SM, Kanovsky M, Ma ZW, Lee WH | title = Association of human Pur alpha with the retinoblastoma protein, Rb, regulates binding to the single-stranded DNA Pur alpha recognition element | journal = The Journal of Biological Chemistry | volume = 270 | issue = 41 | pages = 24352–60 | date = October 1995 | pmid = 7592647 | doi=10.1074/jbc.270.41.24352}}</ref>


=== Role in mammalian brain development and neurological diseases ===
=== Role in mammalian brain development and neurological diseases ===


Studies of genetic inactivation of ''PURA'' in the mouse provided evidence leading to that for ''PURA'' gene disorders in brain disease. Homozygous ''PURA'' knockouts die shortly after birth with severe defects in brain layer development, tissue wasting and movement disorders. Defects in blood cell development are also prominent, and it is not known how these may affect the brain. Heterozygous knockouts do not die early but exhibit seizure-like disorders.<ref name="ref12972605" /> In rat hippocampal neurons, Pur-alpha is found in the cytoplasm together with mRNA transcripts, in a complex including non-coding RNAs, Pur-beta, fragile X mental retardation proteins and microtubule-associated proteins. This complex is transported by a kinesin motor<ref name="ref15312650">{{cite journal | vauthors = Kanai Y, Dohmae N, Hirokawa N | title = Kinesin transports RNA: isolation and characterization of an RNA-transporting granule | journal = Neuron | volume = 43 | issue = 4 | pages = 513–25 | date = August 2004 | pmid = 15312650 | doi = 10.1016/j.neuron.2004.07.022 }}</ref><ref name="ref11032728">{{cite journal | vauthors = Kobayashi S, Agui K, Kamo S, Li Y, Anzai K | title = Neural BC1 RNA associates with pur alpha, a single-stranded DNA and RNA binding protein, which is involved in the transcription of the BC1 RNA gene | journal = Biochemical and Biophysical Research Communications | volume = 277 | issue = 2 | pages = 341–7 | date = October 2000 | pmid = 11032728 | doi = 10.1006/bbrc.2000.3683 }}</ref> to sites of translation at junctions of nerve cell dendrites.<ref name="ref16511857">{{cite journal | vauthors = Johnson EM, Kinoshita Y, Weinreb DB, Wortman MJ, Simon R, Khalili K, Winckler B, Gordon J | title = Role of Pur alpha in targeting mRNA to sites of translation in hippocampal neuronal dendrites | journal = Journal of Neuroscience Research | volume = 83 | issue = 6 | pages = 929–43 | date = May 2006 | pmid = 16511857 | doi = 10.1002/jnr.20806 }}</ref> Recently ''PURA'' mutations have been found in multiple patients with brain disorders of a similar phenotype including hypotonia, developmental delay, movement disorders, and seizure or seizure-like movements.<ref name="ref25439098">{{cite journal | vauthors = Lalani SR, Zhang J, Schaaf CP, Brown CW, Magoulas P, Tsai AC, El-Gharbawy A, Wierenga KJ, Bartholomew D, Fong CT, Barbaro-Dieber T, Kukolich MK, Burrage LC, Austin E, Keller K, Pastore M, Fernandez F, Lotze T, Wilfong A, Purcarin G, Zhu W, Craigen WJ, McGuire M, Jain M, Cooney E, Azamian M, Bainbridge MN, Muzny DM, Boerwinkle E, Person RE, Niu Z, Eng CM, Lupski JR, Gibbs RA, Beaudet AL, Yang Y, Wang MC, Xia F | display-authors = 6 | title = Mutations in PURA cause profound neonatal hypotonia, seizures, and encephalopathy in 5q31.3 microdeletion syndrome | journal = American Journal of Human Genetics | volume = 95 | issue = 5 | pages = 579–83 | date = November 2014 | pmid = 25439098 | pmc = 4225583 | doi = 10.1016/j.ajhg.2014.09.014 }}</ref><ref name="ref25342064">{{cite journal | vauthors = Hunt D, Leventer RJ, Simons C, Taft R, Swoboda KJ, Gawne-Cain M, Magee AC, Turnpenny PD, Baralle D | title = Whole exome sequencing in family trios reveals de novo mutations in PURA as a cause of severe neurodevelopmental delay and learning disability | journal = Journal of Medical Genetics | volume = 51 | issue = 12 | pages = 806–13 | date = December 2014 | pmid = 25342064 | pmc = 4251168 | doi = 10.1136/jmedgenet-2014-102798 }}</ref><ref name="ref27148565">{{cite journal|last1=Tanaka|first1=AJ|last2=Bai|first2=R|last3=Cho|first3=MT|last4=Anyane-Yeboa|first4=K|last5=Ahimaz|first5=P|last6=Wilson|first6=AL|last7=Kendall|first7=F|last8=Hay|first8=B|last9=Moss|first9=T|last10=Nardini|first10=M|last11=Bauer|first11=M|last12=Retterer|first12=K|last13=Juusola|first13=J|last14=Chung|first14=WK|title=De novo mutations in PURA are associated with hypotonia and developmental delay.|journal=Cold Spring Harbor molecular case studies|date=October 2015|volume=1|issue=1|pages=a000356|pmid=27148565}}</ref> This spectrum of brain disorders is similar to the phenotype of a central nervous system syndrome termed the 5q31.3 microdeletion syndrome,<ref name="ref25439098" /> and is the basis for a proposed ''PURA'' Syndrome<ref>{{cite journal|last1=Reijnders|first1=MRF|last2=Leventer|first2=RJ|last3=Lee|first3=BH|last4=Baralle|first4=D|last5=Selber|first5=P|last6=Paciorkowski|first6=AR|last7=Hunt|first7=D|last8=Pagon|first8=RA|last9=Adam|first9=MP|last10=Ardinger|first10=HH|last11=Wallace|first11=SE|last12=Amemiya|first12=A|last13=Bean|first13=LJH|last14=Bird|first14=TD|last15=Ledbetter|first15=N|last16=Mefford|first16=HC|last17=Smith|first17=RJH|last18=Stephens|first18=K|title=''PURA''-Related Neurodevelopmental Disorders|date=1993|pmid=28448108}}</ref> based on ''PURA'' mutations rather than just deletions.
Studies of genetic inactivation of ''PURA'' in the mouse provided evidence leading to that for ''PURA'' gene disorders in brain disease. Homozygous ''PURA'' knockouts die shortly after birth with severe defects in brain layer development, tissue wasting and movement disorders. Defects in blood cell development are also prominent, and it is not known how these may affect the brain. Heterozygous knockouts do not die early but exhibit seizure-like disorders.<ref name="ref12972605" /> In rat hippocampal neurons, Pur-alpha is found in the cytoplasm together with mRNA transcripts, in a complex including non-coding RNAs, Pur-beta, fragile X mental retardation proteins and microtubule-associated proteins. This complex is transported by a kinesin motor<ref name="ref15312650">{{cite journal | vauthors = Kanai Y, Dohmae N, Hirokawa N | title = Kinesin transports RNA: isolation and characterization of an RNA-transporting granule | journal = Neuron | volume = 43 | issue = 4 | pages = 513–25 | date = August 2004 | pmid = 15312650 | doi = 10.1016/j.neuron.2004.07.022 }}</ref><ref name="ref11032728">{{cite journal | vauthors = Kobayashi S, Agui K, Kamo S, Li Y, Anzai K | title = Neural BC1 RNA associates with pur alpha, a single-stranded DNA and RNA binding protein, which is involved in the transcription of the BC1 RNA gene | journal = Biochemical and Biophysical Research Communications | volume = 277 | issue = 2 | pages = 341–7 | date = October 2000 | pmid = 11032728 | doi = 10.1006/bbrc.2000.3683 }}</ref> to sites of translation at junctions of nerve cell dendrites.<ref name="ref16511857">{{cite journal | vauthors = Johnson EM, Kinoshita Y, Weinreb DB, Wortman MJ, Simon R, Khalili K, Winckler B, Gordon J | title = Role of Pur alpha in targeting mRNA to sites of translation in hippocampal neuronal dendrites | journal = Journal of Neuroscience Research | volume = 83 | issue = 6 | pages = 929–43 | date = May 2006 | pmid = 16511857 | doi = 10.1002/jnr.20806 }}</ref> Recently ''PURA'' mutations have been found in multiple patients with brain disorders of a similar phenotype including hypotonia, developmental delay, movement disorders, and seizure or seizure-like movements.<ref name="ref25439098">{{cite journal | vauthors = Lalani SR, Zhang J, Schaaf CP, Brown CW, Magoulas P, Tsai AC, El-Gharbawy A, Wierenga KJ, Bartholomew D, Fong CT, Barbaro-Dieber T, Kukolich MK, Burrage LC, Austin E, Keller K, Pastore M, Fernandez F, Lotze T, Wilfong A, Purcarin G, Zhu W, Craigen WJ, McGuire M, Jain M, Cooney E, Azamian M, Bainbridge MN, Muzny DM, Boerwinkle E, Person RE, Niu Z, Eng CM, Lupski JR, Gibbs RA, Beaudet AL, Yang Y, Wang MC, Xia F | display-authors = 6 | title = Mutations in PURA cause profound neonatal hypotonia, seizures, and encephalopathy in 5q31.3 microdeletion syndrome | journal = American Journal of Human Genetics | volume = 95 | issue = 5 | pages = 579–83 | date = November 2014 | pmid = 25439098 | pmc = 4225583 | doi = 10.1016/j.ajhg.2014.09.014 }}</ref><ref name="ref25342064">{{cite journal | vauthors = Hunt D, Leventer RJ, Simons C, Taft R, Swoboda KJ, Gawne-Cain M, Magee AC, Turnpenny PD, Baralle D | title = Whole exome sequencing in family trios reveals de novo mutations in PURA as a cause of severe neurodevelopmental delay and learning disability | journal = Journal of Medical Genetics | volume = 51 | issue = 12 | pages = 806–13 | date = December 2014 | pmid = 25342064 | pmc = 4251168 | doi = 10.1136/jmedgenet-2014-102798 }}</ref><ref name="ref27148565">{{cite journal|last1=Tanaka|first1=AJ|last2=Bai|first2=R|last3=Cho|first3=MT|last4=Anyane-Yeboa|first4=K|last5=Ahimaz|first5=P|last6=Wilson|first6=AL|last7=Kendall|first7=F|last8=Hay|first8=B|last9=Moss|first9=T|last10=Nardini|first10=M|last11=Bauer|first11=M|last12=Retterer|first12=K|last13=Juusola|first13=J|last14=Chung|first14=WK|title=De novo mutations in PURA are associated with hypotonia and developmental delay.|journal=Cold Spring Harbor molecular case studies|date=October 2015|volume=1|issue=1|pages=a000356|pmid=27148565|doi=10.1101/mcs.a000356|pmc=4850890}}</ref> This spectrum of brain disorders is similar to the phenotype of a central nervous system syndrome termed the 5q31.3 microdeletion syndrome,<ref name="ref25439098" /> and is the basis for a proposed ''PURA'' Syndrome<ref>{{cite journal|last1=Reijnders|first1=MRF|last2=Leventer|first2=RJ|last3=Lee|first3=BH|last4=Baralle|first4=D|last5=Selber|first5=P|last6=Paciorkowski|first6=AR|last7=Hunt|first7=D|last8=Pagon|first8=RA|last9=Adam|first9=MP|last10=Ardinger|first10=HH|last11=Wallace|first11=SE|last12=Amemiya|first12=A|last13=Bean|first13=LJH|last14=Bird|first14=TD|last15=Ledbetter|first15=N|last16=Mefford|first16=HC|last17=Smith|first17=RJH|last18=Stephens|first18=K|title=''PURA''-Related Neurodevelopmental Disorders|date=1993|pmid=28448108}}</ref> based on ''PURA'' mutations rather than just deletions.


=== Influence on HIV-1 replication ===
=== Influence on HIV-1 replication ===


In the brain Pur-alpha plays a role in diseases involving glial cells, cells that support nerve cells, as well as diseases involving nerve cells. These diseases include neuro-AIDS. Pur-alpha binds to a regulatory RNA element, called TAR, in the HIV-1 genome.<ref name="ref9524214">{{cite journal | vauthors = Chepenik LG, Tretiakova AP, Krachmarov CP, Johnson EM, Khalili K | title = The single-stranded DNA binding protein, Pur-alpha, binds HIV-1 TAR RNA and activates HIV-1 transcription | journal = Gene | volume = 210 | issue = 1 | pages = 37–44 | date = March 1998 | pmid = 9524214 }}</ref> This activates the expression of Tat, a transcriptional activator of its own gene. Pur-alpha binds TAR, allowing Tat to bind an adjacent TAR site to stimulate transcription. Pur-alpha then binds to the Tat protein itself. Pur-alpha also binds Cyclin T1, a regulatory partner of Cdk9 protein kinase, necessary for Tat activity. Cyclin T1/Cdk9 phosphorylates a region of RNA polymerase II. Such phosphorylation of the polymerase enhances its ability to complete RNA synthesis and stimulates replication of the HIV-1 RNA genome.<ref name="ref19182532">{{cite journal | vauthors = White MK, Johnson EM, Khalili K | title = Multiple roles for Puralpha in cellular and viral regulation | journal = Cell Cycle | volume = 8 | issue = 3 | pages = 1–7 | date = February 2009 | pmid = 19182532 | pmc = 2683411 }}</ref><ref>{{cite web|title=SMART: PUR domain annotation|url=http://smart.embl.de/smart/do_annotation.pl?DOMAIN=SM00712|website=smart.embl.de|language=en}}</ref>
In the brain Pur-alpha plays a role in diseases involving glial cells, cells that support nerve cells, as well as diseases involving nerve cells. These diseases include neuro-AIDS. Pur-alpha binds to a regulatory RNA element, called TAR, in the HIV-1 genome.<ref name="ref9524214">{{cite journal | vauthors = Chepenik LG, Tretiakova AP, Krachmarov CP, Johnson EM, Khalili K | title = The single-stranded DNA binding protein, Pur-alpha, binds HIV-1 TAR RNA and activates HIV-1 transcription | journal = Gene | volume = 210 | issue = 1 | pages = 37–44 | date = March 1998 | pmid = 9524214 | doi=10.1016/s0378-1119(98)00033-x}}</ref> This activates the expression of Tat, a transcriptional activator of its own gene. Pur-alpha binds TAR, allowing Tat to bind an adjacent TAR site to stimulate transcription. Pur-alpha then binds to the Tat protein itself. Pur-alpha also binds Cyclin T1, a regulatory partner of Cdk9 protein kinase, necessary for Tat activity. Cyclin T1/Cdk9 phosphorylates a region of RNA polymerase II. Such phosphorylation of the polymerase enhances its ability to complete RNA synthesis and stimulates replication of the HIV-1 RNA genome.<ref name="ref19182532">{{cite journal | vauthors = White MK, Johnson EM, Khalili K | title = Multiple roles for Puralpha in cellular and viral regulation | journal = Cell Cycle | volume = 8 | issue = 3 | pages = 1–7 | date = February 2009 | pmid = 19182532 | pmc = 2683411 | doi=10.4161/cc.8.3.7585}}</ref><ref>{{cite web|title=SMART: PUR domain annotation|url=http://smart.embl.de/smart/do_annotation.pl?DOMAIN=SM00712|website=smart.embl.de|language=en}}</ref>


=== Cooperative effect with HIV-1 on JC polyomavirus replication and expression ===
=== Cooperative effect with HIV-1 on JC polyomavirus replication and expression ===


Pur-alpha participates in development of progressive multifocal leukoencephalopathy (PML), a loss of the nerve sheath formed by oligodendroglial cells.<ref name="ref7862639">{{cite journal | vauthors = Chen NN, Chang CF, Gallia GL, Kerr DA, Johnson EM, Krachmarov CP, Barr SM, Frisque RJ, Bollag B, Khalili K | title = Cooperative action of cellular proteins YB-1 and Pur alpha with the tumor antigen of the human JC polyomavirus determines their interaction with the viral lytic control element | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 4 | pages = 1087–91 | date = February 1995 | pmid = 7862639 | pmc = 42642 }}</ref><ref name="ref8943069">{{cite journal | vauthors = Krachmarov CP, Chepenik LG, Barr-Vagell S, Khalili K, Johnson EM | title = Activation of the JC virus Tat-responsive transcriptional control element by association of the Tat protein of human immunodeficiency virus 1 with cellular protein Pur alpha | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 24 | pages = 14112–7 | date = November 1996 | pmid = 8943069 | pmc = 34556 }}</ref><ref name="ref19182532" /> Although HIV-1 is not usually found in these glial cells, HIV-1 proteins can pass through cell membranes to enter them. JCV is considered the causative agent of PML. JCV is activated in the glial cells by certain states of immune system suppression, including HIV-1 infection.<ref>{{cite journal|last1=Berger|first1=JR|last2=Chauhan|first2=A|last3=Galey|first3=D|last4=Nath|first4=A|title=Epidemiological evidence and molecular basis of interactions between HIV and JC virus.|journal=Journal of NeuroVirology|date=August 2001|volume=7|issue=4|pages=329–38|pmid=11517412}}</ref> There is a documented interaction between Pur-alpha, the HIV-1 protein, Tat, and a Pur-alpha-binding regulatory sequence in JCV DNA.<ref name="ref8943069" /> Pur-alpha acts by altering both replication and gene expression of JCV.<ref name="ref7862639" /><ref name="ref15684713">{{cite journal | vauthors = Daniel DC, Kinoshita Y, Khan MA, Del Valle L, Khalili K, Rappaport J, Johnson EM | title = Internalization of exogenous human immunodeficiency virus-1 protein, Tat, by KG-1 oligodendroglioma cells followed by stimulation of DNA replication initiated at the JC virus origin | journal = DNA and Cell Biology | volume = 23 | issue = 12 | pages = 858–67 | date = December 2004 | pmid = 15684713 | doi = 10.1089/dna.2004.23.858 }}</ref><ref name="ref11413364">{{cite journal | vauthors = Daniel DC, Wortman MJ, Schiller RJ, Liu H, Gan L, Mellen JS, Chang CF, Gallia GL, Rappaport J, Khalili K, Johnson EM | title = Coordinate effects of human immunodeficiency virus type 1 protein Tat and cellular protein Puralpha on DNA replication initiated at the JC virus origin | journal = The Journal of General Virology | volume = 82 | issue = Pt 7 | pages = 1543–53 | date = July 2001 | pmid = 11413364 | doi = 10.1099/0022-1317-82-7-1543 }}</ref><ref name="ref8943069" /><ref name="ref10679817">{{cite journal | vauthors = Wortman MJ, Krachmarov CP, Kim JH, Gordon RG, Chepenik LG, Brady JN, Gallia GL, Khalili K, Johnson EM | title = Interaction of HIV-1 Tat with Puralpha in nuclei of human glial cells: characterization of RNA-mediated protein-protein binding | journal = Journal of Cellular Biochemistry | volume = 77 | issue = 1 | pages = 65–74 | date = February 2000 | pmid = 10679817 }}</ref>
Pur-alpha participates in development of progressive multifocal leukoencephalopathy (PML), a loss of the nerve sheath formed by oligodendroglial cells.<ref name="ref7862639">{{cite journal | vauthors = Chen NN, Chang CF, Gallia GL, Kerr DA, Johnson EM, Krachmarov CP, Barr SM, Frisque RJ, Bollag B, Khalili K | title = Cooperative action of cellular proteins YB-1 and Pur alpha with the tumor antigen of the human JC polyomavirus determines their interaction with the viral lytic control element | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 4 | pages = 1087–91 | date = February 1995 | pmid = 7862639 | pmc = 42642 | doi=10.1073/pnas.92.4.1087}}</ref><ref name="ref8943069">{{cite journal | vauthors = Krachmarov CP, Chepenik LG, Barr-Vagell S, Khalili K, Johnson EM | title = Activation of the JC virus Tat-responsive transcriptional control element by association of the Tat protein of human immunodeficiency virus 1 with cellular protein Pur alpha | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 24 | pages = 14112–7 | date = November 1996 | pmid = 8943069 | pmc = 34556 | doi=10.1073/pnas.93.24.14112}}</ref><ref name="ref19182532" /> Although HIV-1 is not usually found in these glial cells, HIV-1 proteins can pass through cell membranes to enter them. JCV is considered the causative agent of PML. JCV is activated in the glial cells by certain states of immune system suppression, including HIV-1 infection.<ref>{{cite journal|last1=Berger|first1=JR|last2=Chauhan|first2=A|last3=Galey|first3=D|last4=Nath|first4=A|title=Epidemiological evidence and molecular basis of interactions between HIV and JC virus.|journal=Journal of NeuroVirology|date=August 2001|volume=7|issue=4|pages=329–38|pmid=11517412|doi=10.1080/13550280152537193}}</ref> There is a documented interaction between Pur-alpha, the HIV-1 protein, Tat, and a Pur-alpha-binding regulatory sequence in JCV DNA.<ref name="ref8943069" /> Pur-alpha acts by altering both replication and gene expression of JCV.<ref name="ref7862639" /><ref name="ref15684713">{{cite journal | vauthors = Daniel DC, Kinoshita Y, Khan MA, Del Valle L, Khalili K, Rappaport J, Johnson EM | title = Internalization of exogenous human immunodeficiency virus-1 protein, Tat, by KG-1 oligodendroglioma cells followed by stimulation of DNA replication initiated at the JC virus origin | journal = DNA and Cell Biology | volume = 23 | issue = 12 | pages = 858–67 | date = December 2004 | pmid = 15684713 | doi = 10.1089/dna.2004.23.858 }}</ref><ref name="ref11413364">{{cite journal | vauthors = Daniel DC, Wortman MJ, Schiller RJ, Liu H, Gan L, Mellen JS, Chang CF, Gallia GL, Rappaport J, Khalili K, Johnson EM | title = Coordinate effects of human immunodeficiency virus type 1 protein Tat and cellular protein Puralpha on DNA replication initiated at the JC virus origin | journal = The Journal of General Virology | volume = 82 | issue = Pt 7 | pages = 1543–53 | date = July 2001 | pmid = 11413364 | doi = 10.1099/0022-1317-82-7-1543 }}</ref><ref name="ref8943069" /><ref name="ref10679817">{{cite journal | vauthors = Wortman MJ, Krachmarov CP, Kim JH, Gordon RG, Chepenik LG, Brady JN, Gallia GL, Khalili K, Johnson EM | title = Interaction of HIV-1 Tat with Puralpha in nuclei of human glial cells: characterization of RNA-mediated protein-protein binding | journal = Journal of Cellular Biochemistry | volume = 77 | issue = 1 | pages = 65–74 | date = February 2000 | pmid = 10679817 | doi=10.1002/(sici)1097-4644(20000401)77:1<65::aid-jcb7>3.0.co;2-u}}</ref>


=== Role in amyotrophic lateral sclerosis (ALS) ===
=== Role in amyotrophic lateral sclerosis (ALS) ===


Pur-alpha plays a role in ALS, otherwise known as Lou Gehrig’s disease. ALS is a motor neuron disease involving both the brain and spinal cord, resulting in progressive loss of muscle control. ALS has several contributing causes, but the most common familial form is due to an expanded repeat of the hexanucleotide GGGGCC at the chromosomal locus ''C9ORF72''.<ref name="ref22406228">{{cite journal | vauthors = Majounie E, Renton AE, Mok K, Dopper EG, Waite A, Rollinson S, Chiò A, Restagno G, Nicolaou N, Simon-Sanchez J, van Swieten JC, Abramzon Y, Johnson JO, Sendtner M, Pamphlett R, Orrell RW, Mead S, Sidle KC, Houlden H, Rohrer JD, Morrison KE, Pall H, Talbot K, Ansorge O, Hernandez DG, Arepalli S, Sabatelli M, Mora G, Corbo M, Giannini F, Calvo A, Englund E, Borghero G, Floris GL, Remes AM, Laaksovirta H, McCluskey L, Trojanowski JQ, Van Deerlin VM, Schellenberg GD, Nalls MA, Drory VE, Lu CS, Yeh TH, Ishiura H, Takahashi Y, Tsuji S, Le Ber I, Brice A, Drepper C, Williams N, Kirby J, Shaw P, Hardy J, Tienari PJ, Heutink P, Morris HR, Pickering-Brown S, Traynor BJ | display-authors = 6 | title = Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study | journal = The Lancet. Neurology | volume = 11 | issue = 4 | pages = 323–30 | date = April 2012 | pmid = 22406228 | pmc = 3322422 | doi = 10.1016/S1474-4422(12)70043-1 }}</ref><ref name="ref23553836">{{cite journal | vauthors = Xu Z, Poidevin M, Li X, Li Y, Shu L, Nelson DL, Li H, Hales CM, Gearing M, Wingo TS, Jin P | title = Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 19 | pages = 7778–83 | date = May 2013 | pmid = 23553836 | pmc = 3651485 | doi = 10.1073/pnas.1219643110 }}</ref> The ''C9ORF72'' hexanucleotide repeat expansion (HRE) is capable of binding Pur-alpha very tightly. Pur-alpha may act in ALS directly by binding this DNA repeat expansion or its single-stranded RNA transcript.<ref name="ref25788698">{{cite journal | vauthors = Rossi S, Serrano A, Gerbino V, Giorgi A, Di Francesco L, Nencini M, Bozzo F, Schininà ME, Bagni C, Cestra G, Carrì MT, Achsel T, Cozzolino M | display-authors = 6 | title = Nuclear accumulation of mRNAs underlies G4C2-repeat-induced translational repression in a cellular model of C9orf72 ALS | journal = Journal of Cell Science | volume = 128 | issue = 9 | pages = 1787–99 | date = May 2015 | pmid = 25788698 | doi = 10.1242/jcs.165332 }}</ref><ref name="ref23553836" /> One potential consequence of this binding would be to influence an unconventional translation of this transcript repeat that results in long dipeptide repeats. This is termed RAN (Repeat Associated Non-ATG) translation initiation.<ref name="ref23415312">{{cite journal | vauthors = Ash PE, Bieniek KF, Gendron TF, Caulfield T, Lin WL, Dejesus-Hernandez M, van Blitterswijk MM, Jansen-West K, Paul JW, Rademakers R, Boylan KB, Dickson DW, Petrucelli L | display-authors = 6 | title = Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS | journal = Neuron | volume = 77 | issue = 4 | pages = 639–46 | date = February 2013 | pmid = 23415312 | pmc = 3593233 | doi = 10.1016/j.neuron.2013.02.004 }}</ref> Aberrant Pur-alpha association with its RNA sequence segment may also be a feature of ALS types that do not involve ''C9ORF72'' expansion.<ref name="ref26728149">{{cite journal | vauthors = Daigle JG, Krishnamurthy K, Ramesh N, Casci I, Monaghan J, McAvoy K, Godfrey EW, Daniel DC, Johnson EM, Monahan Z, Shewmaker F, Pasinelli P, Pandey UB | display-authors = 6 | title = Pur-alpha regulates cytoplasmic stress granule dynamics and ameliorates FUS toxicity | journal = Acta Neuropathologica | volume = 131 | issue = 4 | pages = 605–20 | date = April 2016 | pmid = 26728149 | pmc = 4791193 | doi = 10.1007/s00401-015-1530-0 }}</ref> Addition of Pur-alpha suppresses neurodegeneration in mouse neuronal cells and in Drosophila expressing the ''C9ORF72'' HRE.<ref name="ref23553836" /> Pur-alpha also reverses neuronal changes caused by defects in the gene, ''FUS'', which can lead to ALS.<ref name="ref26728149" /><ref>{{cite web|title=Stress Granules Need Pur-alpha to Come Together|url=http://www.alsresearchforum.org/stress-granules-need-pur-alpha-to-come-together/|website=Research ALS}}</ref> The mechanism of action of Pur-alpha in ALS is not known. There is presently no evidence that the ''PURA'' sequence itself is mutated in the ''C9ORF72'' form of ALS. Rather, it is a regulatory nucleic acid sequence to which Pur-alpha binds that is altered.
Pur-alpha plays a role in ALS, otherwise known as Lou Gehrig’s disease. ALS is a motor neuron disease involving both the brain and spinal cord, resulting in progressive loss of muscle control. ALS has several contributing causes, but the most common familial form is due to an expanded repeat of the hexanucleotide GGGGCC at the chromosomal locus ''C9ORF72''.<ref name="ref22406228">{{cite journal | vauthors = Majounie E, Renton AE, Mok K, Dopper EG, Waite A, Rollinson S, Chiò A, Restagno G, Nicolaou N, Simon-Sanchez J, van Swieten JC, Abramzon Y, Johnson JO, Sendtner M, Pamphlett R, Orrell RW, Mead S, Sidle KC, Houlden H, Rohrer JD, Morrison KE, Pall H, Talbot K, Ansorge O, Hernandez DG, Arepalli S, Sabatelli M, Mora G, Corbo M, Giannini F, Calvo A, Englund E, Borghero G, Floris GL, Remes AM, Laaksovirta H, McCluskey L, Trojanowski JQ, Van Deerlin VM, Schellenberg GD, Nalls MA, Drory VE, Lu CS, Yeh TH, Ishiura H, Takahashi Y, Tsuji S, Le Ber I, Brice A, Drepper C, Williams N, Kirby J, Shaw P, Hardy J, Tienari PJ, Heutink P, Morris HR, Pickering-Brown S, Traynor BJ | display-authors = 6 | title = Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study | journal = The Lancet. Neurology | volume = 11 | issue = 4 | pages = 323–30 | date = April 2012 | pmid = 22406228 | pmc = 3322422 | doi = 10.1016/S1474-4422(12)70043-1 }}</ref><ref name="ref23553836">{{cite journal | vauthors = Xu Z, Poidevin M, Li X, Li Y, Shu L, Nelson DL, Li H, Hales CM, Gearing M, Wingo TS, Jin P | title = Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 19 | pages = 7778–83 | date = May 2013 | pmid = 23553836 | pmc = 3651485 | doi = 10.1073/pnas.1219643110 }}</ref> The ''C9ORF72'' hexanucleotide repeat expansion (HRE) is capable of binding Pur-alpha very tightly. Pur-alpha may act in ALS directly by binding this DNA repeat expansion or its single-stranded RNA transcript.<ref name="ref25788698">{{cite journal | vauthors = Rossi S, Serrano A, Gerbino V, Giorgi A, Di Francesco L, Nencini M, Bozzo F, Schininà ME, Bagni C, Cestra G, Carrì MT, Achsel T, Cozzolino M | display-authors = 6 | title = Nuclear accumulation of mRNAs underlies G4C2-repeat-induced translational repression in a cellular model of C9orf72 ALS | journal = Journal of Cell Science | volume = 128 | issue = 9 | pages = 1787–99 | date = May 2015 | pmid = 25788698 | doi = 10.1242/jcs.165332 }}</ref><ref name="ref23553836" /> One potential consequence of this binding would be to influence an unconventional translation of this transcript repeat that results in long dipeptide repeats. This is termed RAN (Repeat Associated Non-ATG) translation initiation.<ref name="ref23415312">{{cite journal | vauthors = Ash PE, Bieniek KF, Gendron TF, Caulfield T, Lin WL, Dejesus-Hernandez M, van Blitterswijk MM, Jansen-West K, Paul JW, Rademakers R, Boylan KB, Dickson DW, Petrucelli L | display-authors = 6 | title = Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS | journal = Neuron | volume = 77 | issue = 4 | pages = 639–46 | date = February 2013 | pmid = 23415312 | pmc = 3593233 | doi = 10.1016/j.neuron.2013.02.004 }}</ref> Aberrant Pur-alpha association with its RNA sequence segment may also be a feature of ALS types that do not involve ''C9ORF72'' expansion.<ref name="ref26728149">{{cite journal | vauthors = Daigle JG, Krishnamurthy K, Ramesh N, Casci I, Monaghan J, McAvoy K, Godfrey EW, Daniel DC, Johnson EM, Monahan Z, Shewmaker F, Pasinelli P, Pandey UB | display-authors = 6 | title = Pur-alpha regulates cytoplasmic stress granule dynamics and ameliorates FUS toxicity | journal = Acta Neuropathologica | volume = 131 | issue = 4 | pages = 605–20 | date = April 2016 | pmid = 26728149 | pmc = 4791193 | doi = 10.1007/s00401-015-1530-0 }}</ref> Addition of Pur-alpha suppresses neurodegeneration in mouse neuronal cells and in Drosophila expressing the ''C9ORF72'' HRE.<ref name="ref23553836" /> Pur-alpha also reverses neuronal changes caused by defects in the gene, ''FUS'', which can lead to ALS.<ref name="ref26728149" /><ref>{{cite web|title=Stress Granules Need Pur-alpha to Come Together|url=http://www.alsresearchforum.org/stress-granules-need-pur-alpha-to-come-together/|website=Research ALS}}</ref> The mechanism of action of Pur-alpha in ALS is not known. There is presently no evidence that the ''PURA'' sequence itself is mutated in the ''C9ORF72'' form of ALS. Rather, it is a regulatory nucleic acid sequence to which Pur-alpha binds that is altered.
==Notes==
{{Academic-written review
| wikidate =
| journal = [[Gene (journal)|Gene]]
| title  = {{#property:P1476|from=Q46703061}}
| authors = {{#property:P2093|from=Q46703061}}
| date    = {{#property:P577|from=Q46703061}}
| volume  = {{#property:P478|from=Q46703061}}
| issue  = {{#property:P433|from=Q46703061}}
| pages  = {{#property:P304|from=Q46703061}}
| doi    = {{#property:P356|from=Q46703061}}
| pmid    = {{#property:P698|from=Q46703061}}
| pmc    = {{#property:P932|from=Q46703061}}
}}


== References ==
== References ==
Line 40: Line 55:
== Further reading ==
== Further reading ==
{{refbegin|33em}}
{{refbegin|33em}}
* {{cite journal | vauthors = Barbe MF, Krueger JJ, Loomis R, Otte J, Gordon J | title = Memory deficits, gait ataxia and neuronal loss in the hippocampus and cerebellum in mice that are heterozygous for Pur-alpha | journal = Neuroscience | volume = 337 | pages = 177–190 | date = November 2016 | pmid = 27651147 |  doi = 10.1016/j.neuroscience.2016.09.018 }}
* {{cite journal | vauthors = Barbe MF, Krueger JJ, Loomis R, Otte J, Gordon J | title = Memory deficits, gait ataxia and neuronal loss in the hippocampus and cerebellum in mice that are heterozygous for Pur-alpha | journal = Neuroscience | volume = 337 | pages = 177–190 | date = November 2016 | pmid = 27651147 |  doi = 10.1016/j.neuroscience.2016.09.018 | pmc=5458736}}
* {{cite journal | vauthors = Sariyer IK, Sariyer R, Otte J, Gordon J | title = Pur-alpha induces JCV gene expression and viral replication by suppressing SRSF1 in Glial Cells | journal = PLoS One | volume = 11 | issue = 6 | pages = e0156819 | date = 2016 | pmid = 27257867 | pmc = 4892494| doi = 10.1371/journal.pone.0156819 }}
* {{cite journal | vauthors = Sariyer IK, Sariyer R, Otte J, Gordon J | title = Pur-alpha induces JCV gene expression and viral replication by suppressing SRSF1 in Glial Cells | journal = PLOS ONE | volume = 11 | issue = 6 | pages = e0156819 | date = 2016 | pmid = 27257867 | pmc = 4892494| doi = 10.1371/journal.pone.0156819 }}
* {{cite journal | vauthors = Weber J, Bao H, Hartlmuller C, Wang Z, Windhager A, Janowski R, Madl T, Jin P, Niessing D | title = Structural basis of nucleic acid recognition and double-strand unwinding by the essential neuronal protein Pur-alpha | journal = Elife | volume = 5 | date = 2016 | pmid = 26744780 | doi = 10.7554/eLife.11297 }}
* {{cite journal | vauthors = Weber J, Bao H, Hartlmuller C, Wang Z, Windhager A, Janowski R, Madl T, Jin P, Niessing D | title = Structural basis of nucleic acid recognition and double-strand unwinding by the essential neuronal protein Pur-alpha | journal = eLife | volume = 5 | date = 2016 | pmid = 26744780 | doi = 10.7554/eLife.11297 | pmc=4764581}}
* {{cite journal | vauthors = Peruzzi F, Gordon J, Darbinian N, Amini S | title = Tat-induced deregulation of neuronal differentiation and survival by nerve growth factor pathway | journal = Journal of Neurovirology | volume = 8 Suppl 2 | issue = 2 | pages = 91–6 | date = December 2002 | pmid = 12491158 | doi = 10.1080/13550280290167885 }}
* {{cite journal | vauthors = Peruzzi F, Gordon J, Darbinian N, Amini S | title = Tat-induced deregulation of neuronal differentiation and survival by nerve growth factor pathway | journal = Journal of Neurovirology | volume = 8 Suppl 2 | issue = 2 | pages = 91–6 | date = December 2002 | pmid = 12491158 | doi = 10.1080/13550280290167885 }}
* {{cite journal | vauthors = Gallia GL, Johnson EM, Khalili K | title = Puralpha: a multifunctional single-stranded DNA- and RNA-binding protein | journal = Nucleic Acids Research | volume = 28 | issue = 17 | pages = 3197–205 | date = September 2000 | pmid = 10954586 | pmc = 110688 | doi = 10.1093/nar/28.17.3197 }}
* {{cite journal | vauthors = Gallia GL, Johnson EM, Khalili K | title = Puralpha: a multifunctional single-stranded DNA- and RNA-binding protein | journal = Nucleic Acids Research | volume = 28 | issue = 17 | pages = 3197–205 | date = September 2000 | pmid = 10954586 | pmc = 110688 | doi = 10.1093/nar/28.17.3197 }}

Latest revision as of 14:30, 29 June 2018

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Pur-alpha is a protein that in humans is encoded by the PURA gene[1] located at chromosome 5, band q31.[2][3]

Pur-alpha an ancient, multi-functional DNA- and RNA-binding protein.[1][4] PURA is expressed in every human tissue. Human Pur-alpha is a protein of 322 amino acids. According to convention, PURA, the gene, is written italicized in all upper case letters. Pur-alpha, the protein, is written with the first letter capitalized and can be found listed as Pur-alpha, Pur-α, Pura, Puralpha, Pur alpha and Pur1.

Evolutionary conservation and function

Pur-alpha was the first sequence-specific single-stranded DNA-binding protein to be discovered in higher organisms (GenBank M96684.1; GI:190749).[1] It binds to both single-stranded and double-stranded DNA, making contact with G residues in the purine-rich strand of its binding site. Cumulative data shows that Pur-alpha preferentially binds to the sequence (G2-4N1-3)n, where N is not G. N denotes a nucleotide, and n denotes the number of repeats of this small sequence. N may be repeated up to three times in this sequence.[1][5] Following the identification of a Pur factor, which specifically bound a purine-rich sequence in the control region of the c-MYC gene,[6] the gene, PURA, encoding the protein, Pur-alpha, was cloned and sequenced for both human[1] and mouse (GenBank U02098.1).[4] Pur-alpha belongs to the four-member Pur protein family, which also includes Pur-beta (GenBank AY039216.1; GI:14906267)[1] and two forms of Pur–gamma (Variant A, GenBank AF195513.2; Variant B, GenBank AY077841).[7]

Pur protein sequences from bacteria through humans contain an amino acid segment that is strongly conserved (see NCBI smart00712).[1][8] Human Pur-alpha contains three repeats of this Pur domain and bacterial Pur-alpha contains one.[1][9] This evolutionary conservation means that the specific sequence of this domain is important for the survival of most species throughout the spectrum of living organisms. This essential nature of the Pur domain piques interest because the functions of Pur-alpha in lower organisms and in humans differ greatly. For example, Pur-alpha is essential for brain and blood cell development in mammals,[10] but bacteria have no brain and no blood. In humans Pur-alpha functions to activate transcription in the nucleus, to facilitate RNA transport in the cytoplasm and to regulate DNA replication in the cell cycle.[8] In certain functions Pur-alpha interacts with family member Pur-beta.[11][12] Several cell cycle regulatory functions may be mediated by Pur-alpha binding to Cyclin/Cdk protein kinases, which phosphorylate proteins regulating cell cycle transition points.[13][14] Requirements for Pur-alpha in all organisms are united by Pur-alpha’s ability to bind nucleic acids coupled to its ability to interact with regulatory and transport proteins.

Relevance in human diseases

Genetic perturbation in leukemia and anti-proliferative effect

PURA, located at chromosome 5 band q31, is frequently deleted in myelodysplastic syndrome (MDS),[15] a disorder of white blood cells, that may progress to acute myelogenous leukemia (AML).[2] Loss of one copy of chromosome 7 is also frequent in MDS. PURB, the gene encoding Pur-beta, is located at 7p13. A visual fluorescence analysis of chromosomes from MDS patients shows that deletions of PURA at 5q31 are more strongly linked to progression of MDS to AML when combined with deletions of the PURB gene, including complete loss of chromosome 7.[2] All of the PURA deletions noted, involve only one of the two paired, parentally-derived chromosomes. The implication is that Pur-alpha and -beta are each codominantly expressed, and that haploid levels are insufficient for a protective effect against cancer. All known PURA deletions in people occur in only one of the two copies of chromosome 5.[16]

Inducing increased levels of Pur-alpha in several different cultured cancer cell lines blocks cell proliferation. It also blocks anchorage-independent colony formation, a hallmark of cancer.[13][17] This is true whether Pur-alpha is microinjected or expressed after introducing a cloned PURA cDNA into cells.[18] The Pur-alpha inhibition of cancer cell proliferation occurs at specific points in the cell division cycle, primarily at checkpoints for transition to DNA replication or mitosis.[18] These cell cycle effects are consistent with an interaction between Pur-alpha and CDK, cell cycle-dependent protein kinases.[13] They are also consistent with documented interaction between Pur-alpha and the tumor suppressor protein, Rb.[19]

Role in mammalian brain development and neurological diseases

Studies of genetic inactivation of PURA in the mouse provided evidence leading to that for PURA gene disorders in brain disease. Homozygous PURA knockouts die shortly after birth with severe defects in brain layer development, tissue wasting and movement disorders. Defects in blood cell development are also prominent, and it is not known how these may affect the brain. Heterozygous knockouts do not die early but exhibit seizure-like disorders.[10] In rat hippocampal neurons, Pur-alpha is found in the cytoplasm together with mRNA transcripts, in a complex including non-coding RNAs, Pur-beta, fragile X mental retardation proteins and microtubule-associated proteins. This complex is transported by a kinesin motor[20][21] to sites of translation at junctions of nerve cell dendrites.[22] Recently PURA mutations have been found in multiple patients with brain disorders of a similar phenotype including hypotonia, developmental delay, movement disorders, and seizure or seizure-like movements.[23][24][25] This spectrum of brain disorders is similar to the phenotype of a central nervous system syndrome termed the 5q31.3 microdeletion syndrome,[23] and is the basis for a proposed PURA Syndrome[26] based on PURA mutations rather than just deletions.

Influence on HIV-1 replication

In the brain Pur-alpha plays a role in diseases involving glial cells, cells that support nerve cells, as well as diseases involving nerve cells. These diseases include neuro-AIDS. Pur-alpha binds to a regulatory RNA element, called TAR, in the HIV-1 genome.[27] This activates the expression of Tat, a transcriptional activator of its own gene. Pur-alpha binds TAR, allowing Tat to bind an adjacent TAR site to stimulate transcription. Pur-alpha then binds to the Tat protein itself. Pur-alpha also binds Cyclin T1, a regulatory partner of Cdk9 protein kinase, necessary for Tat activity. Cyclin T1/Cdk9 phosphorylates a region of RNA polymerase II. Such phosphorylation of the polymerase enhances its ability to complete RNA synthesis and stimulates replication of the HIV-1 RNA genome.[28][29]

Cooperative effect with HIV-1 on JC polyomavirus replication and expression

Pur-alpha participates in development of progressive multifocal leukoencephalopathy (PML), a loss of the nerve sheath formed by oligodendroglial cells.[30][31][28] Although HIV-1 is not usually found in these glial cells, HIV-1 proteins can pass through cell membranes to enter them. JCV is considered the causative agent of PML. JCV is activated in the glial cells by certain states of immune system suppression, including HIV-1 infection.[32] There is a documented interaction between Pur-alpha, the HIV-1 protein, Tat, and a Pur-alpha-binding regulatory sequence in JCV DNA.[31] Pur-alpha acts by altering both replication and gene expression of JCV.[30][33][34][31][35]

Role in amyotrophic lateral sclerosis (ALS)

Pur-alpha plays a role in ALS, otherwise known as Lou Gehrig’s disease. ALS is a motor neuron disease involving both the brain and spinal cord, resulting in progressive loss of muscle control. ALS has several contributing causes, but the most common familial form is due to an expanded repeat of the hexanucleotide GGGGCC at the chromosomal locus C9ORF72.[36][37] The C9ORF72 hexanucleotide repeat expansion (HRE) is capable of binding Pur-alpha very tightly. Pur-alpha may act in ALS directly by binding this DNA repeat expansion or its single-stranded RNA transcript.[38][37] One potential consequence of this binding would be to influence an unconventional translation of this transcript repeat that results in long dipeptide repeats. This is termed RAN (Repeat Associated Non-ATG) translation initiation.[39] Aberrant Pur-alpha association with its RNA sequence segment may also be a feature of ALS types that do not involve C9ORF72 expansion.[40] Addition of Pur-alpha suppresses neurodegeneration in mouse neuronal cells and in Drosophila expressing the C9ORF72 HRE.[37] Pur-alpha also reverses neuronal changes caused by defects in the gene, FUS, which can lead to ALS.[40][41] The mechanism of action of Pur-alpha in ALS is not known. There is presently no evidence that the PURA sequence itself is mutated in the C9ORF72 form of ALS. Rather, it is a regulatory nucleic acid sequence to which Pur-alpha binds that is altered.

Notes


References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Bergemann AD, Ma ZW, Johnson EM (December 1992). "Sequence of cDNA comprising the human pur gene and sequence-specific single-stranded-DNA-binding properties of the encoded protein". Molecular and Cellular Biology. 12 (12): 5673–82. doi:10.1128/mcb.12.12.5673. PMC 360507. PMID 1448097.
  2. ↑ 2.0 2.1 2.2 Lezon-Geyda K, Najfeld V, Johnson EM (June 2001). "Deletions of PURA, at 5q31, and PURB, at 7p13, in myelodysplastic syndrome and progression to acute myelogenous leukemia". Leukemia. 15 (6): 954–62. doi:10.1038/sj.leu.2402108. PMID 11417483.
  3. ↑ Ma ZW, Pejovic T, Najfeld V, Ward DC, Johnson EM (1995). "Localization of PURA, the gene encoding the sequence-specific single-stranded-DNA-binding protein Pur alpha, to chromosome band 5q31". Cytogenetics and Cell Genetics. 71 (1): 64–7. doi:10.1159/000134065. PMID 7606931.
  4. ↑ 4.0 4.1 Ma ZW, Bergemann AD, Johnson EM (November 1994). "Conservation in human and mouse Pur alpha of a motif common to several proteins involved in initiation of DNA replication". Gene. 149 (2): 311–4. doi:10.1016/0378-1119(94)90167-8. PMID 7959008.
  5. ↑ Wortman MJ, Johnson EM, Bergemann AD (March 2005). "Mechanism of DNA binding and localized strand separation by Pur alpha and comparison with Pur family member, Pur beta". Biochimica et Biophysica Acta. 1743 (1–2): 64–78. doi:10.1016/j.bbamcr.2004.08.010. PMID 15777841.
  6. ↑ Bergemann AD, Johnson EM (March 1992). "The HeLa Pur factor binds single-stranded DNA at a specific element conserved in gene flanking regions and origins of DNA replication". Molecular and Cellular Biology. 12 (3): 1257–65. doi:10.1128/mcb.12.3.1257. PMC 369558. PMID 1545807.
  7. ↑ Liu H, Johnson EM (June 2002). "Distinct proteins encoded by alternative transcripts of the PURG gene, located contrapodal to WRN on chromosome 8, determined by differential termination/polyadenylation". Nucleic Acids Research. 30 (11): 2417–26. doi:10.1093/nar/30.11.2417. PMC 117198. PMID 12034829.
  8. ↑ 8.0 8.1 Johnson EM (2003). "The Pur protein family: clues to function from recent studies on cancer and AIDS". Anticancer Research. 23 (3A): 2093–100. PMID 12894583.
  9. ↑ Graebsch A, Roche S, Kostrewa D, Söding J, Niessing D (October 2010). "Of bits and bugs--on the use of bioinformatics and a bacterial crystal structure to solve a eukaryotic repeat-protein structure". PLOS ONE. 5 (10): e13402. doi:10.1371/journal.pone.0013402. PMC 2954813. PMID 20976240.
  10. ↑ 10.0 10.1 Khalili K, Del Valle L, Muralidharan V, Gault WJ, Darbinian N, Otte J, Meier E, Johnson EM, Daniel DC, Kinoshita Y, Amini S, Gordon J (October 2003). "Puralpha is essential for postnatal brain development and developmentally coupled cellular proliferation as revealed by genetic inactivation in the mouse". Molecular and Cellular Biology. 23 (19): 6857–75. doi:10.1128/mcb.23.19.6857-6875.2003. PMC 193944. PMID 12972605.
  11. ↑ Hariharan S, Kelm RJ, Strauch AR (September 2014). "The Purα/Purβ single-strand DNA-binding proteins attenuate smooth-muscle actin gene transactivation in myofibroblasts". Journal of Cellular Physiology. 229 (9): 1256–71. doi:10.1002/jcp.24564. PMID 24446247.
  12. ↑ Kelm RJ, Elder PK, Strauch AR, Getz MJ (October 1997). "Sequence of cDNAs encoding components of vascular actin single-stranded DNA-binding factor 2 establish identity to Puralpha and Purbeta". The Journal of Biological Chemistry. 272 (42): 26727–33. doi:10.1074/jbc.272.42.26727. PMID 9334258.
  13. ↑ 13.0 13.1 13.2 Barr SM, Johnson EM (2001). "Ras-induced colony formation and anchorage-independent growth inhibited by elevated expression of Puralpha in NIH3T3 cells". Journal of Cellular Biochemistry. 81 (4): 621–38. doi:10.1002/jcb.1099. PMID 11329617.
  14. ↑ Liu H, Barr SM, Chu C, Kohtz DS, Kinoshita Y, Johnson EM (March 2005). "Functional interaction of Puralpha with the Cdk2 moiety of cyclin A/Cdk2". Biochemical and Biophysical Research Communications. 328 (4): 851–7. doi:10.1016/j.bbrc.2005.01.038. PMID 15707957.
  15. ↑ Reference, Genetics Home. "PURA gene". Genetics Home Reference.
  16. ↑ Hirai, H (April 2003). "Molecular mechanisms of myelodysplastic syndrome". Japanese journal of clinical oncology. 33 (4): 153–60. doi:10.1093/jjco/hyg037. PMID 12810828.
  17. ↑ Darbinian N, Gallia GL, King J, Del Valle L, Johnson EM, Khalili K (December 2001). "Growth inhibition of glioblastoma cells by human Pur(alpha)". Journal of Cellular Physiology. 189 (3): 334–40. doi:10.1002/jcp.10029. PMID 11748591.
  18. ↑ 18.0 18.1 Stacey DW, Hitomi M, Kanovsky M, Gan L, Johnson EM (July 1999). "Cell cycle arrest and morphological alterations following microinjection of NIH3T3 cells with Pur alpha". Oncogene. 18 (29): 4254–61. doi:10.1038/sj.onc.1202795. PMID 10435638.
  19. ↑ Johnson EM, Chen PL, Krachmarov CP, Barr SM, Kanovsky M, Ma ZW, Lee WH (October 1995). "Association of human Pur alpha with the retinoblastoma protein, Rb, regulates binding to the single-stranded DNA Pur alpha recognition element". The Journal of Biological Chemistry. 270 (41): 24352–60. doi:10.1074/jbc.270.41.24352. PMID 7592647.
  20. ↑ Kanai Y, Dohmae N, Hirokawa N (August 2004). "Kinesin transports RNA: isolation and characterization of an RNA-transporting granule". Neuron. 43 (4): 513–25. doi:10.1016/j.neuron.2004.07.022. PMID 15312650.
  21. ↑ Kobayashi S, Agui K, Kamo S, Li Y, Anzai K (October 2000). "Neural BC1 RNA associates with pur alpha, a single-stranded DNA and RNA binding protein, which is involved in the transcription of the BC1 RNA gene". Biochemical and Biophysical Research Communications. 277 (2): 341–7. doi:10.1006/bbrc.2000.3683. PMID 11032728.
  22. ↑ Johnson EM, Kinoshita Y, Weinreb DB, Wortman MJ, Simon R, Khalili K, Winckler B, Gordon J (May 2006). "Role of Pur alpha in targeting mRNA to sites of translation in hippocampal neuronal dendrites". Journal of Neuroscience Research. 83 (6): 929–43. doi:10.1002/jnr.20806. PMID 16511857.
  23. ↑ 23.0 23.1 Lalani SR, Zhang J, Schaaf CP, Brown CW, Magoulas P, Tsai AC, et al. (November 2014). "Mutations in PURA cause profound neonatal hypotonia, seizures, and encephalopathy in 5q31.3 microdeletion syndrome". American Journal of Human Genetics. 95 (5): 579–83. doi:10.1016/j.ajhg.2014.09.014. PMC 4225583. PMID 25439098.
  24. ↑ Hunt D, Leventer RJ, Simons C, Taft R, Swoboda KJ, Gawne-Cain M, Magee AC, Turnpenny PD, Baralle D (December 2014). "Whole exome sequencing in family trios reveals de novo mutations in PURA as a cause of severe neurodevelopmental delay and learning disability". Journal of Medical Genetics. 51 (12): 806–13. doi:10.1136/jmedgenet-2014-102798. PMC 4251168. PMID 25342064.
  25. ↑ Tanaka, AJ; Bai, R; Cho, MT; Anyane-Yeboa, K; Ahimaz, P; Wilson, AL; Kendall, F; Hay, B; Moss, T; Nardini, M; Bauer, M; Retterer, K; Juusola, J; Chung, WK (October 2015). "De novo mutations in PURA are associated with hypotonia and developmental delay". Cold Spring Harbor molecular case studies. 1 (1): a000356. doi:10.1101/mcs.a000356. PMC 4850890. PMID 27148565.
  26. ↑ Reijnders, MRF; Leventer, RJ; Lee, BH; Baralle, D; Selber, P; Paciorkowski, AR; Hunt, D; Pagon, RA; Adam, MP; Ardinger, HH; Wallace, SE; Amemiya, A; Bean, LJH; Bird, TD; Ledbetter, N; Mefford, HC; Smith, RJH; Stephens, K (1993). "PURA-Related Neurodevelopmental Disorders". PMID 28448108.
  27. ↑ Chepenik LG, Tretiakova AP, Krachmarov CP, Johnson EM, Khalili K (March 1998). "The single-stranded DNA binding protein, Pur-alpha, binds HIV-1 TAR RNA and activates HIV-1 transcription". Gene. 210 (1): 37–44. doi:10.1016/s0378-1119(98)00033-x. PMID 9524214.
  28. ↑ 28.0 28.1 White MK, Johnson EM, Khalili K (February 2009). "Multiple roles for Puralpha in cellular and viral regulation". Cell Cycle. 8 (3): 1–7. doi:10.4161/cc.8.3.7585. PMC 2683411. PMID 19182532.
  29. ↑ "SMART: PUR domain annotation". smart.embl.de.
  30. ↑ 30.0 30.1 Chen NN, Chang CF, Gallia GL, Kerr DA, Johnson EM, Krachmarov CP, Barr SM, Frisque RJ, Bollag B, Khalili K (February 1995). "Cooperative action of cellular proteins YB-1 and Pur alpha with the tumor antigen of the human JC polyomavirus determines their interaction with the viral lytic control element". Proceedings of the National Academy of Sciences of the United States of America. 92 (4): 1087–91. doi:10.1073/pnas.92.4.1087. PMC 42642. PMID 7862639.
  31. ↑ 31.0 31.1 31.2 Krachmarov CP, Chepenik LG, Barr-Vagell S, Khalili K, Johnson EM (November 1996). "Activation of the JC virus Tat-responsive transcriptional control element by association of the Tat protein of human immunodeficiency virus 1 with cellular protein Pur alpha". Proceedings of the National Academy of Sciences of the United States of America. 93 (24): 14112–7. doi:10.1073/pnas.93.24.14112. PMC 34556. PMID 8943069.
  32. ↑ Berger, JR; Chauhan, A; Galey, D; Nath, A (August 2001). "Epidemiological evidence and molecular basis of interactions between HIV and JC virus". Journal of NeuroVirology. 7 (4): 329–38. doi:10.1080/13550280152537193. PMID 11517412.
  33. ↑ Daniel DC, Kinoshita Y, Khan MA, Del Valle L, Khalili K, Rappaport J, Johnson EM (December 2004). "Internalization of exogenous human immunodeficiency virus-1 protein, Tat, by KG-1 oligodendroglioma cells followed by stimulation of DNA replication initiated at the JC virus origin". DNA and Cell Biology. 23 (12): 858–67. doi:10.1089/dna.2004.23.858. PMID 15684713.
  34. ↑ Daniel DC, Wortman MJ, Schiller RJ, Liu H, Gan L, Mellen JS, Chang CF, Gallia GL, Rappaport J, Khalili K, Johnson EM (July 2001). "Coordinate effects of human immunodeficiency virus type 1 protein Tat and cellular protein Puralpha on DNA replication initiated at the JC virus origin". The Journal of General Virology. 82 (Pt 7): 1543–53. doi:10.1099/0022-1317-82-7-1543. PMID 11413364.
  35. ↑ Wortman MJ, Krachmarov CP, Kim JH, Gordon RG, Chepenik LG, Brady JN, Gallia GL, Khalili K, Johnson EM (February 2000). "Interaction of HIV-1 Tat with Puralpha in nuclei of human glial cells: characterization of RNA-mediated protein-protein binding". Journal of Cellular Biochemistry. 77 (1): 65–74. doi:10.1002/(sici)1097-4644(20000401)77:1<65::aid-jcb7>3.0.co;2-u. PMID 10679817.
  36. ↑ Majounie E, Renton AE, Mok K, Dopper EG, Waite A, Rollinson S, et al. (April 2012). "Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study". The Lancet. Neurology. 11 (4): 323–30. doi:10.1016/S1474-4422(12)70043-1. PMC 3322422. PMID 22406228.
  37. ↑ 37.0 37.1 37.2 Xu Z, Poidevin M, Li X, Li Y, Shu L, Nelson DL, Li H, Hales CM, Gearing M, Wingo TS, Jin P (May 2013). "Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration". Proceedings of the National Academy of Sciences of the United States of America. 110 (19): 7778–83. doi:10.1073/pnas.1219643110. PMC 3651485. PMID 23553836.
  38. ↑ Rossi S, Serrano A, Gerbino V, Giorgi A, Di Francesco L, Nencini M, et al. (May 2015). "Nuclear accumulation of mRNAs underlies G4C2-repeat-induced translational repression in a cellular model of C9orf72 ALS". Journal of Cell Science. 128 (9): 1787–99. doi:10.1242/jcs.165332. PMID 25788698.
  39. ↑ Ash PE, Bieniek KF, Gendron TF, Caulfield T, Lin WL, Dejesus-Hernandez M, et al. (February 2013). "Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS". Neuron. 77 (4): 639–46. doi:10.1016/j.neuron.2013.02.004. PMC 3593233. PMID 23415312.
  40. ↑ 40.0 40.1 Daigle JG, Krishnamurthy K, Ramesh N, Casci I, Monaghan J, McAvoy K, et al. (April 2016). "Pur-alpha regulates cytoplasmic stress granule dynamics and ameliorates FUS toxicity". Acta Neuropathologica. 131 (4): 605–20. doi:10.1007/s00401-015-1530-0. PMC 4791193. PMID 26728149.
  41. ↑ "Stress Granules Need Pur-alpha to Come Together". Research ALS.

Further reading

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