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==Haematopoietic stem cell aging==
==Haematopoietic stem cell aging==
Accumulation of DNA damage leading to stem cell exhaustion is regarded as an important aspect of aging.<ref name="pmid17554309">{{cite journal | vauthors = Rossi DJ, Bryder D, Seita J, Nussenzweig A, Hoeijmakers J, Weissman IL | title = Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age | journal = Nature | volume = 447 | issue = 7145 | pages = 725–9 | date = June 2007 | pmid = 17554309 | doi = 10.1038/nature05862 }}</ref><ref>{{cite book | vauthors = Bernstein H, Payne CM, Bernstein C, Garewal H, Dvorak K | year = 2008 | chapter = Chapter 1: Cancer and aging as consequences of un-repaired DNA damage | title =  New Research on DNA Damages | veditors = Kimura  H, Suzuki A | publisher = Nova Science Publishers, Inc. | location = New York | pages = 1–47 | chapter-url =  https://www.novapublishers.com/catalog/product_info.php?products_id=43247 | isbn = 978-1-60456-581-2 }}</ref>  Deficiency of lig4 in pluripotent stem cells impairs [[Non-homologous end joining]] (NHEJ) and results in accumulation of DNA double-strand breaks and enhanced apoptosis.<ref name=Tilgner />  Lig4 deficiency in the mouse causes a progressive loss of haematopoietic stem cells and bone marrow cellularity during aging.<ref name=Nijnik>{{cite journal | vauthors = Nijnik A, Woodbine L, Marchetti C, Dawson S, Lambe T, Liu C, Rodrigues NP, Crockford TL, Cabuy E, Vindigni A, Enver T, Bell JI, Slijepcevic P, Goodnow CC, Jeggo PA, Cornall RJ | title = DNA repair is limiting for haematopoietic stem cells during ageing | journal = Nature | volume = 447 | issue = 7145 | pages = 686–90 | date = June 2007 | pmid = 17554302 | doi = 10.1038/nature05875 }}</ref>  The sensitivity of haematopoietic stem cells to lig4 deficiency suggests that lig4-mediated NHEJ is a key determinant of the ability of stem cells to maintain themselves against physiological stress over time.<ref name=Tilgner /><ref name=Nijnik />
Accumulation of DNA damage leading to stem cell exhaustion is regarded as an important aspect of aging.<ref name="pmid17554309">{{cite journal | vauthors = Rossi DJ, Bryder D, Seita J, Nussenzweig A, Hoeijmakers J, Weissman IL | title = Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age | journal = Nature | volume = 447 | issue = 7145 | pages = 725–9 | date = June 2007 | pmid = 17554309 | doi = 10.1038/nature05862 }}</ref><ref>{{cite book | vauthors = Bernstein H, Payne CM, Bernstein C, Garewal H, Dvorak K | year = 2008 | chapter = Chapter 1: Cancer and aging as consequences of un-repaired DNA damage | title =  New Research on DNA Damages | veditors = Kimura  H, Suzuki A | publisher = [[Nova Science Publishers, Inc.]] | location = New York | pages = 1–47 | chapter-url =  https://www.novapublishers.com/catalog/product_info.php?products_id=43247 | isbn = 978-1-60456-581-2 }}</ref>  Deficiency of lig4 in pluripotent stem cells impairs [[Non-homologous end joining]] (NHEJ) and results in accumulation of DNA double-strand breaks and enhanced apoptosis.<ref name=Tilgner />  Lig4 deficiency in the mouse causes a progressive loss of haematopoietic stem cells and bone marrow cellularity during aging.<ref name=Nijnik>{{cite journal | vauthors = Nijnik A, Woodbine L, Marchetti C, Dawson S, Lambe T, Liu C, Rodrigues NP, Crockford TL, Cabuy E, Vindigni A, Enver T, Bell JI, Slijepcevic P, Goodnow CC, Jeggo PA, Cornall RJ | title = DNA repair is limiting for haematopoietic stem cells during ageing | journal = Nature | volume = 447 | issue = 7145 | pages = 686–90 | date = June 2007 | pmid = 17554302 | doi = 10.1038/nature05875 }}</ref>  The sensitivity of haematopoietic stem cells to lig4 deficiency suggests that lig4-mediated NHEJ is a key determinant of the ability of stem cells to maintain themselves against physiological stress over time.<ref name=Tilgner /><ref name=Nijnik />


== Interactions ==
== Interactions ==
Line 17: Line 17:


==Mechanism==
==Mechanism==
LIG4 is an ATP-dependent DNA ligase.  LIG4 uses ATP to adenylate itself and then transfers the AMP group to the 5' phosphate of one DNA end.  Nucleophilic attack by the 3' hydroxyl group of a second DNA end and release of AMP yield the ligation product.  Adenylation of LIG4 is stimulated by [[XRCC4]] and [[Non-homologous end-joining factor 1|XLF]].<ref name="pmid23442139">{{cite journal | vauthors = Mahaney BL, Hammel M, Meek K, Tainer JA, Lees-Miller SP | title = XRCC4 and XLF form long helical protein filaments suitable for DNA end protection and alignment to facilitate DNA double strand break repair | journal = Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire | volume = 91 | issue = 1 | pages = 31–41 | date = February 2013 | pmid = 23442139 | pmc = 3725335 | doi = 10.1139/bcb-2012-0058 }}</ref>
LIG4 is an ATP-dependent DNA ligase.  LIG4 uses ATP to adenylate itself and then transfers the AMP group to the 5' phosphate of one DNA end.  Nucleophilic attack by the 3' hydroxyl group of a second DNA end and release of AMP yield the ligation product.  Adenylation of LIG4 is stimulated by [[XRCC4]] and [[Non-homologous end-joining factor 1|XLF]].<ref name="pmid23442139">{{cite journal | vauthors = Mahaney BL, Hammel M, Meek K, Tainer JA, Lees-Miller SP | title = XRCC4 and XLF form long helical protein filaments suitable for DNA end protection and alignment to facilitate DNA double strand break repair | journal = Biochemistry and Cell Biology | volume = 91 | issue = 1 | pages = 31–41 | date = February 2013 | pmid = 23442139 | pmc = 3725335 | doi = 10.1139/bcb-2012-0058 }}</ref>


== References ==
== References ==

Latest revision as of 11:30, 9 January 2019

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Identifiers
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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
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DNA ligase 4 is an enzyme that in humans is encoded by the LIG4 gene.[1]

Function

The protein encoded by this gene is an ATP-dependent DNA ligase that joins double-strand breaks during the non-homologous end joining pathway of double-strand break repair. It is also essential for V(D)J recombination. Lig4 forms a complex with XRCC4, and further interacts with the DNA-dependent protein kinase (DNA-PK) and XLF/Cernunnos, which are also required for NHEJ. The crystal structure of the Lig4/XRCC4 complex has been resolved.[2] Defects in this gene are the cause of LIG4 syndrome. The yeast homolog of Lig4 is Dnl4.

LIG4 Syndrome

In humans, deficiency of DNA ligase 4 results in a clinical condition known as LIG4 syndrome. This syndrome is characterized by cellular radiation sensitivity, growth retardation, developmental delay, microcephaly, facial dysmorphisms, increased disposition to leukemia, variable degrees of immunodeficiency and reduced number of blood cells.[3][4]

Haematopoietic stem cell aging

Accumulation of DNA damage leading to stem cell exhaustion is regarded as an important aspect of aging.[5][6] Deficiency of lig4 in pluripotent stem cells impairs Non-homologous end joining (NHEJ) and results in accumulation of DNA double-strand breaks and enhanced apoptosis.[4] Lig4 deficiency in the mouse causes a progressive loss of haematopoietic stem cells and bone marrow cellularity during aging.[7] The sensitivity of haematopoietic stem cells to lig4 deficiency suggests that lig4-mediated NHEJ is a key determinant of the ability of stem cells to maintain themselves against physiological stress over time.[4][7]

Interactions

LIG4 has been shown to interact with XRCC4 via its BRCT domain.[8][2] This interaction stabilizes LIG4 protein in cells; cells that are deficient for XRCC4, such as XR-1 cells, have reduced levels of LIG4.[9]

Mechanism

LIG4 is an ATP-dependent DNA ligase. LIG4 uses ATP to adenylate itself and then transfers the AMP group to the 5' phosphate of one DNA end. Nucleophilic attack by the 3' hydroxyl group of a second DNA end and release of AMP yield the ligation product. Adenylation of LIG4 is stimulated by XRCC4 and XLF.[10]

References

  1. "Entrez Gene: LIG4 ligase IV, DNA, ATP-dependent".
  2. 2.0 2.1 Sibanda BL, Critchlow SE, Begun J, Pei XY, Jackson SP, Blundell TL, Pellegrini L (December 2001). "Crystal structure of an Xrcc4-DNA ligase IV complex". Nature Structural Biology. 8 (12): 1015–9. doi:10.1038/nsb725. PMID 11702069.
  3. Rucci F, Notarangelo LD, Fazeli A, Patrizi L, Hickernell T, Paganini T, Coakley KM, Detre C, Keszei M, Walter JE, Feldman L, Cheng HL, Poliani PL, Wang JH, Balter BB, Recher M, Andersson EM, Zha S, Giliani S, Terhorst C, Alt FW, Yan CT (February 2010). "Homozygous DNA ligase IV R278H mutation in mice leads to leaky SCID and represents a model for human LIG4 syndrome". Proceedings of the National Academy of Sciences of the United States of America. 107 (7): 3024–9. doi:10.1073/pnas.0914865107. PMC 2840307. PMID 20133615.
  4. 4.0 4.1 4.2 Tilgner K, Neganova I, Moreno-Gimeno I, Al-Aama JY, Burks D, Yung S, Singhapol C, Saretzki G, Evans J, Gorbunova V, Gennery A, Przyborski S, Stojkovic M, Armstrong L, Jeggo P, Lako M (August 2013). "A human iPSC model of Ligase IV deficiency reveals an important role for NHEJ-mediated-DSB repair in the survival and genomic stability of induced pluripotent stem cells and emerging haematopoietic progenitors". Cell Death and Differentiation. 20 (8): 1089–100. doi:10.1038/cdd.2013.44. PMC 3705601. PMID 23722522.
  5. Rossi DJ, Bryder D, Seita J, Nussenzweig A, Hoeijmakers J, Weissman IL (June 2007). "Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age". Nature. 447 (7145): 725–9. doi:10.1038/nature05862. PMID 17554309.
  6. Bernstein H, Payne CM, Bernstein C, Garewal H, Dvorak K (2008). "Chapter 1: Cancer and aging as consequences of un-repaired DNA damage". In Kimura H, Suzuki A. New Research on DNA Damages. New York: Nova Science Publishers, Inc. pp. 1–47. ISBN 978-1-60456-581-2.
  7. 7.0 7.1 Nijnik A, Woodbine L, Marchetti C, Dawson S, Lambe T, Liu C, Rodrigues NP, Crockford TL, Cabuy E, Vindigni A, Enver T, Bell JI, Slijepcevic P, Goodnow CC, Jeggo PA, Cornall RJ (June 2007). "DNA repair is limiting for haematopoietic stem cells during ageing". Nature. 447 (7145): 686–90. doi:10.1038/nature05875. PMID 17554302.
  8. Deshpande RA, Wilson TE (October 2007). "Modes of interaction among yeast Nej1, Lif1 and Dnl4 proteins and comparison to human XLF, XRCC4 and Lig4". DNA Repair. 6 (10): 1507–16. doi:10.1016/j.dnarep.2007.04.014. PMC 2064958. PMID 17567543.
  9. Bryans M, Valenzano MC, Stamato TD (January 1999). "Absence of DNA ligase IV protein in XR-1 cells: evidence for stabilization by XRCC4". Mutation Research. 433 (1): 53–8. doi:10.1016/s0921-8777(98)00063-9. PMID 10047779.
  10. Mahaney BL, Hammel M, Meek K, Tainer JA, Lees-Miller SP (February 2013). "XRCC4 and XLF form long helical protein filaments suitable for DNA end protection and alignment to facilitate DNA double strand break repair". Biochemistry and Cell Biology. 91 (1): 31–41. doi:10.1139/bcb-2012-0058. PMC 3725335. PMID 23442139.

Further reading