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{{Infobox_gene}}
{{PBB_Controls
'''DNA damage-binding protein 2''' is a [[protein]] that in humans is encoded by the ''DDB2'' [[gene]].<ref name="pmid8407967">{{cite journal | vauthors = Keeney S, Chang GJ, Linn S | title = Characterization of a human DNA damage binding protein implicated in xeroderma pigmentosum E | journal = The Journal of Biological Chemistry | volume = 268 | issue = 28 | pages = 21293–300 | date = October 1993 | pmid = 8407967 | pmc =  | doi =  }}</ref><ref name="pmid8530102">{{cite journal | vauthors = Dualan R, Brody T, Keeney S, Nichols AF, Admon A, Linn S | title = Chromosomal localization and cDNA cloning of the genes (DDB1 and DDB2) for the p127 and p48 subunits of a human damage-specific DNA binding protein | journal = Genomics | volume = 29 | issue = 1 | pages = 62–9 | date = September 1995 | pmid = 8530102 | pmc = | doi = 10.1006/geno.1995.1215 }}</ref>
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
==Structure==
{{GNF_Protein_box
| image =
| image_source =
| PDB =  
| Name = Damage-specific DNA binding protein 2, 48kDa
| HGNCid = 2718
| Symbol = DDB2
| AltSymbols =; FLJ34321
| OMIM = 600811
| ECnumber = 
| Homologene = 83
| MGIid = 1355314
| GeneAtlas_image1 = PBB_GE_DDB2_203409_at_tn.png
| Function = {{GNF_GO|id=GO:0003684 |text = damaged DNA binding}} {{GNF_GO|id=GO:0005515 |text = protein binding}}
| Component = {{GNF_GO|id=GO:0005634 |text = nucleus}}
| Process = {{GNF_GO|id=GO:0006289 |text = nucleotide-excision repair}} {{GNF_GO|id=GO:0006290 |text = pyrimidine dimer repair}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 1643
    | Hs_Ensembl = ENSG00000134574
    | Hs_RefseqProtein = NP_000098
    | Hs_RefseqmRNA = NM_000107
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 11
    | Hs_GenLoc_start = 47193089
    | Hs_GenLoc_end = 47217339
    | Hs_Uniprot = Q92466
    | Mm_EntrezGene = 107986
    | Mm_Ensembl = ENSMUSG00000002109
    | Mm_RefseqmRNA = NM_028119
    | Mm_RefseqProtein = NP_082395
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 2
    | Mm_GenLoc_start = 91012427
    | Mm_GenLoc_end = 91037746
    | Mm_Uniprot = Q99J79
  }}
}}
'''Damage-specific DNA binding protein 2, 48kDa''', also known as '''DDB2''', is a human [[gene]].


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
As indicated by  Rapić-Otrin et al. in 2003,<ref name=Rapić-Otrin2003>{{cite journal | vauthors = Rapić-Otrin V, Navazza V, Nardo T, Botta E, McLenigan M, Bisi DC, Levine AS, Stefanini M | title = True XP group E patients have a defective UV-damaged DNA binding protein complex and mutations in DDB2 which reveal the functional domains of its p48 product | journal = Human Molecular Genetics | volume = 12 | issue = 13 | pages = 1507–22 | date = July 2003 | pmid = 12812979 | doi =  10.1093/hmg/ddg174}}</ref> the ''DDB2'' gene is located on human chromosome 11p11.2, spans a region of approximately 24 – 26 kb and includes 10 exons.  The DDB2 protein contains five putative [[WD40 repeat]]s (sequences of about 40 [[amino acid]]s that can interact with each other) positioned downstream from the second exon. The WD40 motif identified in DDB2 is characteristic of proteins involved in the recognition of chromatin proteins. The C-terminal region of DDB2 (a 48 kDa molecular weight protein) is essential for binding to DDB1 (a larger 127 kDa protein).  Together, the two proteins form a UV-damaged DNA binding protein complex (UV-DDB).<ref name="pmid12034848">{{cite journal | vauthors = Rapić-Otrin V, McLenigan MP, Bisi DC, Gonzalez M, Levine AS | title = Sequential binding of UV DNA damage binding factor and degradation of the p48 subunit as early events after UV irradiation | journal = Nucleic Acids Research | volume = 30 | issue = 11 | pages = 2588–98 | date = June 2002 | pmid = 12034848 | pmc = 117178 | doi = 10.1093/nar/30.11.2588}}</ref>
{{PBB_Summary
| section_title =  
| summary_text = DDB2 is the smaller subunit of a heterodimeric protein implicated in the etiology of xeroderma pigmentosum group E. This subunit appears to be required for DNA binding.<ref name="entrez">{{cite web | title = Entrez Gene: DDB2 damage-specific DNA binding protein 2, 48kDa| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1643| accessdate = }}</ref>
}}


==References==
==Deficiency in humans==
{{reflist|2}}
 
==Further reading==
If humans have a mutation in each copy of their ''DDB2'' gene, this causes a mild form of the human disease [[xeroderma pigmentosum]], called XPE.<ref name=Rapić-Otrin2003 /> Patients in the XPE group have mild dermatological manifestations and are neurologically unaffected. Mutation in the ''DDB2'' gene causes a deficiency in [[nucleotide excision repair]] of DNA. This deficiency is also mild, showing 40 to 60% of normal repair capability and a modest sensitivity to UV light in comparison to the sensitivities of cells defective in the other XP genes [[XPA]], [[XPB]], [[XPC (gene)|XPC]], [[ERCC2|XPD]], [[ERCC4|XPF]] and [[Xeroderma pigmentosum|XPG]].<ref name="pmid9584159">{{cite journal | vauthors = Rapić Otrin V, Kuraoka I, Nardo T, McLenigan M, Eker AP, Stefanini M, Levine AS, Wood RD | title = Relationship of the xeroderma pigmentosum group E DNA repair defect to the chromatin and DNA binding proteins UV-DDB and replication protein A | journal = Molecular and Cellular Biology | volume = 18 | issue = 6 | pages = 3182–90 | date = June 1998 | pmid = 9584159 | pmc = 108900 | doi = 10.1128/mcb.18.6.3182}}</ref>
{{refbegin | 2}}
 
{{PBB_Further_reading
== Function ==
| citations =
 
*{{cite journal | author=El-Deiry WS |title=Transactivation of repair genes by BRCA1. |journal=Cancer Biol. Ther. |volume=1 |issue= 5 |pages= 490-1 |year= 2003 |pmid= 12496474 |doi= }}
===Binding to damaged DNA===
*{{cite journal | author=Qian YW, Wang YC, Hollingsworth RE, ''et al.'' |title=A retinoblastoma-binding protein related to a negative regulator of Ras in yeast. |journal=Nature |volume=364 |issue= 6438 |pages= 648-52 |year= 1993 |pmid= 8350924 |doi= 10.1038/364648a0 }}
 
*{{cite journal  | author=Keeney S, Chang GJ, Linn S |title=Characterization of a human DNA damage binding protein implicated in xeroderma pigmentosum E. |journal=J. Biol. Chem. |volume=268 |issue= 28 |pages= 21293-300 |year= 1993 |pmid= 8407967 |doi=  }}
As shown by Wittschieben et al.,<ref name="pmid16223728">{{cite journal | vauthors = Wittschieben BØ, Iwai S, Wood RD | title = DDB1-DDB2 (xeroderma pigmentosum group E) protein complex recognizes a cyclobutane pyrimidine dimer, mismatches, apurinic/apyrimidinic sites, and compound lesions in DNA | journal = The Journal of Biological Chemistry | volume = 280 | issue = 48 | pages = 39982–9 | date = December 2005 | pmid = 16223728 | doi = 10.1074/jbc.M507854200 }}</ref> when DDB2 is in a complex with DDB1, forming the heterodimer DDB, this complex binds strongly to DNA containing one type of  UV light-induced [[pyrimidine dimer|photoproduct]] [the (6-4) photoproduct], to DNA with an abasic site, to DNA containing mismatches without a covalent lesion, and to “compound” lesions containing both mismatches and lesions. The heterodimer DDB binds with intermediate strength to DNA containing another UV light-induced photoproduct (the cyclobutane pyrimidine dimer), and binds weakly to DNA that has no DNA damage. The DDB2 component of the heterodimer contains the specificity for binding to damaged DNA, since a heterodimer DDB complex containing amino acid substitutions in the DDB2 subunit, as found in XP-E patients, is very deficient in binding to damaged DNA. DDB1 and DDB2, each acting alone, do not bind DNA.
*{{cite journal | author=Dualan R, Brody T, Keeney S, ''et al.'' |title=Chromosomal localization and cDNA cloning of the genes (DDB1 and DDB2) for the p127 and p48 subunits of a human damage-specific DNA binding protein. |journal=Genomics |volume=29 |issue= 1 |pages= 62-9 |year= 1996 |pmid= 8530102 |doi= 10.1006/geno.1995.1215 }}
 
*{{cite journal  | author=Taunton J, Hassig CA, Schreiber SL |title=A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. |journal=Science |volume=272 |issue= 5260 |pages= 408-11 |year= 1996 |pmid= 8602529 |doi= }}
===Chromatin remodeling===
*{{cite journal  | author=Nichols AF, Ong P, Linn S |title=Mutations specific to the xeroderma pigmentosum group E Ddb- phenotype. |journal=J. Biol. Chem. |volume=271 |issue= 40 |pages= 24317-20 |year= 1996 |pmid= 8798680 |doi= }}
 
*{{cite journal  | author=Hayes S, Shiyanov P, Chen X, Raychaudhuri P |title=DDB, a putative DNA repair protein, can function as a transcriptional partner of E2F1. |journal=Mol. Cell. Biol. |volume=18 |issue= 1 |pages= 240-9 |year= 1998 |pmid= 9418871 |doi= }}
The packaging of eukaryotic DNA into [[chromatin]] presents a barrier to all DNA-based processes that require recruitment of enzymes to their sites of action. To allow the critical cellular process of DNA repair, the chromatin must be relaxed.
*{{cite journal  | author=Martinez E, Palhan VB, Tjernberg A, ''et al.'' |title=Human STAGA complex is a chromatin-acetylating transcription coactivator that interacts with pre-mRNA splicing and DNA damage-binding factors in vivo. |journal=Mol. Cell. Biol. |volume=21 |issue= 20 |pages= 6782-95 |year= 2001 |pmid= 11564863 |doi= 10.1128/MCB.21.20.6782-6795.2001 }}
 
*{{cite journal | author=Chen X, Zhang Y, Douglas L, Zhou P |title=UV-damaged DNA-binding proteins are targets of CUL-4A-mediated ubiquitination and degradation. |journal=J. Biol. Chem. |volume=276 |issue= 51 |pages= 48175-82 |year= 2002 |pmid= 11673459 |doi= 10.1074/jbc.M106808200 }}
DDB2, in its heterodimeric complex with DDB1, and further complexed with the [[ubiquitin ligase]] protein [[CUL4A]]<ref name=Luijsterburg2007>{{cite journal | vauthors = Luijsterburg MS, Goedhart J, Moser J, Kool H, Geverts B, Houtsmuller AB, Mullenders LH, Vermeulen W, van Driel R | title = Dynamic in vivo interaction of DDB2 E3 ubiquitin ligase with UV-damaged DNA is independent of damage-recognition protein XPC | journal = Journal of Cell Science | volume = 120 | issue = Pt 15 | pages = 2706–16 | date = August 2007 | pmid = 17635991 | doi = 10.1242/jcs.008367 }}</ref> and with [[PARP1]]<ref name=Pines>{{cite journal | vauthors = Pines A, Vrouwe MG, Marteijn JA, Typas D, Luijsterburg MS, Cansoy M, Hensbergen P, Deelder A, de Groot A, Matsumoto S, Sugasawa K, Thoma N, Vermeulen W, Vrieling H, Mullenders L | title = PARP1 promotes nucleotide excision repair through DDB2 stabilization and recruitment of ALC1 | journal = The Journal of Cell Biology | volume = 199 | issue = 2 | pages = 235–49 | date = October 2012 | pmid = 23045548 | pmc = 3471223 | doi = 10.1083/jcb.201112132 }}</ref> rapidly associates with UV-induced damage within chromatin, with half-maximum association completed in 40 seconds.<ref name=Luijsterburg2007 /> The PARP1 protein, attached to both DDB1 and DDB2, then [[ADP-ribosylation#Poly ADP-ribosylation|PARylates]] (creates a poly-ADP ribose chain) on DDB2 that attracts the DNA remodeling protein [[CHD1L|ALC1]].<ref name=Pines />  Action of ALC1 relaxes the chromatin at the site of UV damage to DNA. This relaxation allows other proteins in the [[nucleotide excision repair]] pathway to enter the chromatin and repair the DNA damaged by the UV-induced presence of cyclobutane pyrimidine dimers.
*{{cite journal  | author=Sun NK, Kamarajan P, Huang H, Chao CC |title=Restoration of UV sensitivity in UV-resistant HeLa cells by antisense-mediated depletion of damaged DNA-binding protein 2 (DDB2). |journal=FEBS Lett. |volume=512 |issue= 1-3 |pages= 168-72 |year= 2002 |pmid= 11852074 |doi= }}
 
*{{cite journal  | author=Tan T, Chu G |title=p53 Binds and activates the xeroderma pigmentosum DDB2 gene in humans but not mice. |journal=Mol. Cell. Biol. |volume=22 |issue= 10 |pages= 3247-54 |year= 2002 |pmid= 11971958 |doi= }}
===Other functions===
*{{cite journal | author=Rapić-Otrin V, McLenigan MP, Bisi DC, ''et al.'' |title=Sequential binding of UV DNA damage binding factor and degradation of the p48 subunit as early events after UV irradiation. |journal=Nucleic Acids Res. |volume=30 |issue= 11 |pages= 2588-98 |year= 2002 |pmid= 12034848 |doi= }}
 
*{{cite journal  | author=Bergametti F, Sitterlin D, Transy C |title=Turnover of hepatitis B virus X protein is regulated by damaged DNA-binding complex. |journal=J. Virol. |volume=76 |issue= 13 |pages= 6495-501 |year= 2002 |pmid= 12050362 |doi= }}
In 2015, Zhu et al.<ref name="pmid26255936">{{cite journal | vauthors = Zhu Q, Battu A, Ray A, Wani G, Qian J, He J, Wang QE, Wani AA | title = Damaged DNA-binding protein down-regulates epigenetic mark H3K56Ac through histone deacetylase 1 and 2 | journal = Mutation Research | volume = 776 | issue = | pages = 16–23 | date = June 2015 | pmid = 26255936 | pmc = 5053336 | doi = 10.1016/j.mrfmmm.2015.01.005 }}</ref> showed that DDB2 down-regulates the acetylation of lysine 56 in histone H3 (H3K56Ac) after UV-induced DNA damage through DDB2 interaction with [[histone deacetylase]]s 1 and 2.  Decreased acetylation of histones decreases transcription of associated genes in the DNA wrapped around the histones.
*{{cite journal  | author=Bontron S, Lin-Marq N, Strubin M |title=Hepatitis B virus X protein associated with UV-DDB1 induces cell death in the nucleus and is functionally antagonized by UV-DDB2. |journal=J. Biol. Chem. |volume=277 |issue= 41 |pages= 38847-54 |year= 2002 |pmid= 12151405 |doi= 10.1074/jbc.M205722200 }}
 
*{{cite journal | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
In 2016, Zou et al.<ref name="pmid27553023">{{cite journal | vauthors = Zou N, Xie G, Cui T, Srivastava AK, Qu M, Yang L, Wei S, Zheng Y, Wang QE | title = DDB2 increases radioresistance of NSCLC cells by enhancing DNA damage responses | journal = Tumour Biology | volume = 37 | issue = 10 | pages = 14183–14191 | date = October 2016 | pmid = 27553023 | doi = 10.1007/s13277-016-5203-y }}</ref> showed that DDB2 is involved in cell cycle arrest and [[homologous recombination]]al DNA repair after cells are subjected to ionizing radiation.
*{{cite journal | author=Sun NK, Lu HP, Chao CC |title=Overexpression of damaged-DNA-binding protein 2 (DDB2) potentiates UV resistance in hamster V79 cells. |journal=Chang Gung medical journal |volume=25 |issue= 11 |pages= 723-33 |year= 2003 |pmid= 12553360 |doi= }}
 
*{{cite journal | author=Groisman R, Polanowska J, Kuraoka I, ''et al.'' |title=The ubiquitin ligase activity in the DDB2 and CSA complexes is differentially regulated by the COP9 signalosome in response to DNA damage. |journal=Cell |volume=113 |issue= 3 |pages= 357-67 |year= 2003 |pmid= 12732143 |doi= }}
In 2016, Christmann et al.<ref name="pmid27694624">{{cite journal | vauthors = Christmann M, Boisseau C, Kitzinger R, Berac C, Allmann S, Sommer T, Aasland D, Kaina B, Tomicic MT | title = Adaptive upregulation of DNA repair genes following benzo(a)pyrene diol epoxide protects against cell death at the expense of mutations | journal = Nucleic Acids Research | volume = 44 | issue = 22 | pages = 10727–10743 | date = December 2016 | pmid = 27694624 | pmc = 5159553 | doi = 10.1093/nar/gkw873 }}</ref> showed that exposure of cells to the carcinogenic benzo(a)pyrene metabolite BPDE caused prompt and sustained upregulation of DDB2.  This contributed to enhanced removal of BPDE [[adduct]]s from DNA.
*{{cite journal | author=Rapić-Otrin V, Navazza V, Nardo T, ''et al.'' |title=True XP group E patients have a defective UV-damaged DNA binding protein complex and mutations in DDB2 which reveal the functional domains of its p48 product. |journal=Hum. Mol. Genet. |volume=12 |issue= 13 |pages= 1507-22 |year= 2004 |pmid= 12812979 |doi= }}
 
*{{cite journal | author=Fitch ME, Nakajima S, Yasui A, Ford JM |title=In vivo recruitment of XPC to UV-induced cyclobutane pyrimidine dimers by the DDB2 gene product. |journal=J. Biol. Chem. |volume=278 |issue= 47 |pages= 46906-10 |year= 2004 |pmid= 12944386 |doi= 10.1074/jbc.M307254200 }}
In 2017, Fantini et al.<ref name="pmid28035050">{{cite journal | vauthors = Fantini D, Huang S, Asara JM, Bagchi S, Raychaudhuri P | title = Chromatin association of XRCC5/6 in the absence of DNA damage depends on the XPE gene product DDB2 | journal = Molecular Biology of the Cell | volume = 28 | issue = 1 | pages = 192–200 | date = January 2017 | pmid = 28035050 | pmc = 5221623 | doi = 10.1091/mbc.E16-08-0573 }}</ref> showed that DDB2, in association with [[XRCC5]] and [[XRCC6]] (otherwise known as [[Ku80]] and [[Ku70]], which make up the [[Ku (protein)|Ku heterodimer]]), has [[Transcription (biology)|transcription]]al activities. The DDB2/Ku effects on transcription are separate from the actions of the Ku heterodimer in [[non-homologous end joining]] DNA repair.
}}
 
== References ==
{{Reflist|33em}}
 
== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = El-Deiry WS | title = Transactivation of repair genes by BRCA1 | journal = Cancer Biology & Therapy | volume = 1 | issue = 5 | pages = 490–1 | year = 2003 | pmid = 12496474 | doi = 10.4161/cbt.1.5.162 }}
* {{cite journal | vauthors = Qian YW, Wang YC, Hollingsworth RE, Jones D, Ling N, Lee EY | title = A retinoblastoma-binding protein related to a negative regulator of Ras in yeast | journal = Nature | volume = 364 | issue = 6438 | pages = 648–52 | date = August 1993 | pmid = 8350924 | doi = 10.1038/364648a0 }}
* {{cite journal | vauthors = Taunton J, Hassig CA, Schreiber SL | title = A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p | journal = Science | volume = 272 | issue = 5260 | pages = 408–11 | date = April 1996 | pmid = 8602529 | doi = 10.1126/science.272.5260.408 }}
* {{cite journal | vauthors = Nichols AF, Ong P, Linn S | title = Mutations specific to the xeroderma pigmentosum group E Ddb- phenotype | journal = The Journal of Biological Chemistry | volume = 271 | issue = 40 | pages = 24317–20 | date = October 1996 | pmid = 8798680 | doi = 10.1074/jbc.271.40.24317 }}
* {{cite journal | vauthors = Hayes S, Shiyanov P, Chen X, Raychaudhuri P | title = DDB, a putative DNA repair protein, can function as a transcriptional partner of E2F1 | journal = Molecular and Cellular Biology | volume = 18 | issue = 1 | pages = 240–9 | date = January 1998 | pmid = 9418871 | pmc = 121483 | doi = 10.1128/mcb.18.1.240 }}
* {{cite journal | vauthors = Martinez E, Palhan VB, Tjernberg A, Lymar ES, Gamper AM, Kundu TK, Chait BT, Roeder RG | title = Human STAGA complex is a chromatin-acetylating transcription coactivator that interacts with pre-mRNA splicing and DNA damage-binding factors in vivo | journal = Molecular and Cellular Biology | volume = 21 | issue = 20 | pages = 6782–95 | date = October 2001 | pmid = 11564863 | pmc = 99856 | doi = 10.1128/MCB.21.20.6782-6795.2001 }}
* {{cite journal | vauthors = Chen X, Zhang Y, Douglas L, Zhou P | title = UV-damaged DNA-binding proteins are targets of CUL-4A-mediated ubiquitination and degradation | journal = The Journal of Biological Chemistry | volume = 276 | issue = 51 | pages = 48175–82 | date = December 2001 | pmid = 11673459 | doi = 10.1074/jbc.M106808200 }}
* {{cite journal | vauthors = Sun NK, Kamarajan P, Huang H, Chao CC | title = Restoration of UV sensitivity in UV-resistant HeLa cells by antisense-mediated depletion of damaged DNA-binding protein 2 (DDB2) | journal = FEBS Letters | volume = 512 | issue = 1-3 | pages = 168–72 | date = February 2002 | pmid = 11852074 | doi = 10.1016/S0014-5793(02)02250-0 }}
* {{cite journal | vauthors = Tan T, Chu G | title = p53 Binds and activates the xeroderma pigmentosum DDB2 gene in humans but not mice | journal = Molecular and Cellular Biology | volume = 22 | issue = 10 | pages = 3247–54 | date = May 2002 | pmid = 11971958 | pmc = 133779 | doi = 10.1128/MCB.22.10.3247-3254.2002 }}
* {{cite journal | vauthors = Rapić-Otrin V, McLenigan MP, Bisi DC, Gonzalez M, Levine AS | title = Sequential binding of UV DNA damage binding factor and degradation of the p48 subunit as early events after UV irradiation | journal = Nucleic Acids Research | volume = 30 | issue = 11 | pages = 2588–98 | date = June 2002 | pmid = 12034848 | pmc = 117178 | doi = 10.1093/nar/30.11.2588 }}
* {{cite journal | vauthors = Bergametti F, Sitterlin D, Transy C | title = Turnover of hepatitis B virus X protein is regulated by damaged DNA-binding complex | journal = Journal of Virology | volume = 76 | issue = 13 | pages = 6495–501 | date = July 2002 | pmid = 12050362 | pmc = 136256 | doi = 10.1128/JVI.76.13.6495-6501.2002 }}
* {{cite journal | vauthors = Bontron S, Lin-Marq N, Strubin M | title = Hepatitis B virus X protein associated with UV-DDB1 induces cell death in the nucleus and is functionally antagonized by UV-DDB2 | journal = The Journal of Biological Chemistry | volume = 277 | issue = 41 | pages = 38847–54 | date = October 2002 | pmid = 12151405 | doi = 10.1074/jbc.M205722200 }}
* {{cite journal | vauthors = Sun NK, Lu HP, Chao CC | title = Overexpression of damaged-DNA-binding protein 2 (DDB2) potentiates UV resistance in hamster V79 cells | journal = Chang Gung Medical Journal | volume = 25 | issue = 11 | pages = 723–33 | date = November 2002 | pmid = 12553360 | doi =  }}
* {{cite journal | vauthors = Groisman R, Polanowska J, Kuraoka I, Sawada J, Saijo M, Drapkin R, Kisselev AF, Tanaka K, Nakatani Y | title = The ubiquitin ligase activity in the DDB2 and CSA complexes is differentially regulated by the COP9 signalosome in response to DNA damage | journal = Cell | volume = 113 | issue = 3 | pages = 357–67 | date = May 2003 | pmid = 12732143 | doi = 10.1016/S0092-8674(03)00316-7 }}
* {{cite journal | vauthors = Rapić-Otrin V, Navazza V, Nardo T, Botta E, McLenigan M, Bisi DC, Levine AS, Stefanini M | title = True XP group E patients have a defective UV-damaged DNA binding protein complex and mutations in DDB2 which reveal the functional domains of its p48 product | journal = Human Molecular Genetics | volume = 12 | issue = 13 | pages = 1507–22 | date = July 2003 | pmid = 12812979 | doi = 10.1093/hmg/ddg174 }}
* {{cite journal | vauthors = Fitch ME, Nakajima S, Yasui A, Ford JM | title = In vivo recruitment of XPC to UV-induced cyclobutane pyrimidine dimers by the DDB2 gene product | journal = The Journal of Biological Chemistry | volume = 278 | issue = 47 | pages = 46906–10 | date = November 2003 | pmid = 12944386 | doi = 10.1074/jbc.M307254200 }}
{{refend}}
{{refend}}


{{protein-stub}}
== External links ==
{{WikiDoc Sources}}
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=xp  GeneReviews/NIH/NCBI/UW entry on Xeroderma Pigmentosum]

Latest revision as of 09:46, 27 January 2018

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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DNA damage-binding protein 2 is a protein that in humans is encoded by the DDB2 gene.[1][2]

Structure

As indicated by Rapić-Otrin et al. in 2003,[3] the DDB2 gene is located on human chromosome 11p11.2, spans a region of approximately 24 – 26 kb and includes 10 exons. The DDB2 protein contains five putative WD40 repeats (sequences of about 40 amino acids that can interact with each other) positioned downstream from the second exon. The WD40 motif identified in DDB2 is characteristic of proteins involved in the recognition of chromatin proteins. The C-terminal region of DDB2 (a 48 kDa molecular weight protein) is essential for binding to DDB1 (a larger 127 kDa protein). Together, the two proteins form a UV-damaged DNA binding protein complex (UV-DDB).[4]

Deficiency in humans

If humans have a mutation in each copy of their DDB2 gene, this causes a mild form of the human disease xeroderma pigmentosum, called XPE.[3] Patients in the XPE group have mild dermatological manifestations and are neurologically unaffected. Mutation in the DDB2 gene causes a deficiency in nucleotide excision repair of DNA. This deficiency is also mild, showing 40 to 60% of normal repair capability and a modest sensitivity to UV light in comparison to the sensitivities of cells defective in the other XP genes XPA, XPB, XPC, XPD, XPF and XPG.[5]

Function

Binding to damaged DNA

As shown by Wittschieben et al.,[6] when DDB2 is in a complex with DDB1, forming the heterodimer DDB, this complex binds strongly to DNA containing one type of UV light-induced photoproduct [the (6-4) photoproduct], to DNA with an abasic site, to DNA containing mismatches without a covalent lesion, and to “compound” lesions containing both mismatches and lesions. The heterodimer DDB binds with intermediate strength to DNA containing another UV light-induced photoproduct (the cyclobutane pyrimidine dimer), and binds weakly to DNA that has no DNA damage. The DDB2 component of the heterodimer contains the specificity for binding to damaged DNA, since a heterodimer DDB complex containing amino acid substitutions in the DDB2 subunit, as found in XP-E patients, is very deficient in binding to damaged DNA. DDB1 and DDB2, each acting alone, do not bind DNA.

Chromatin remodeling

The packaging of eukaryotic DNA into chromatin presents a barrier to all DNA-based processes that require recruitment of enzymes to their sites of action. To allow the critical cellular process of DNA repair, the chromatin must be relaxed.

DDB2, in its heterodimeric complex with DDB1, and further complexed with the ubiquitin ligase protein CUL4A[7] and with PARP1[8] rapidly associates with UV-induced damage within chromatin, with half-maximum association completed in 40 seconds.[7] The PARP1 protein, attached to both DDB1 and DDB2, then PARylates (creates a poly-ADP ribose chain) on DDB2 that attracts the DNA remodeling protein ALC1.[8] Action of ALC1 relaxes the chromatin at the site of UV damage to DNA. This relaxation allows other proteins in the nucleotide excision repair pathway to enter the chromatin and repair the DNA damaged by the UV-induced presence of cyclobutane pyrimidine dimers.

Other functions

In 2015, Zhu et al.[9] showed that DDB2 down-regulates the acetylation of lysine 56 in histone H3 (H3K56Ac) after UV-induced DNA damage through DDB2 interaction with histone deacetylases 1 and 2. Decreased acetylation of histones decreases transcription of associated genes in the DNA wrapped around the histones.

In 2016, Zou et al.[10] showed that DDB2 is involved in cell cycle arrest and homologous recombinational DNA repair after cells are subjected to ionizing radiation.

In 2016, Christmann et al.[11] showed that exposure of cells to the carcinogenic benzo(a)pyrene metabolite BPDE caused prompt and sustained upregulation of DDB2. This contributed to enhanced removal of BPDE adducts from DNA.

In 2017, Fantini et al.[12] showed that DDB2, in association with XRCC5 and XRCC6 (otherwise known as Ku80 and Ku70, which make up the Ku heterodimer), has transcriptional activities. The DDB2/Ku effects on transcription are separate from the actions of the Ku heterodimer in non-homologous end joining DNA repair.

References

  1. ↑ Keeney S, Chang GJ, Linn S (October 1993). "Characterization of a human DNA damage binding protein implicated in xeroderma pigmentosum E". The Journal of Biological Chemistry. 268 (28): 21293–300. PMID 8407967.
  2. ↑ Dualan R, Brody T, Keeney S, Nichols AF, Admon A, Linn S (September 1995). "Chromosomal localization and cDNA cloning of the genes (DDB1 and DDB2) for the p127 and p48 subunits of a human damage-specific DNA binding protein". Genomics. 29 (1): 62–9. doi:10.1006/geno.1995.1215. PMID 8530102.
  3. ↑ 3.0 3.1 Rapić-Otrin V, Navazza V, Nardo T, Botta E, McLenigan M, Bisi DC, Levine AS, Stefanini M (July 2003). "True XP group E patients have a defective UV-damaged DNA binding protein complex and mutations in DDB2 which reveal the functional domains of its p48 product". Human Molecular Genetics. 12 (13): 1507–22. doi:10.1093/hmg/ddg174. PMID 12812979.
  4. ↑ Rapić-Otrin V, McLenigan MP, Bisi DC, Gonzalez M, Levine AS (June 2002). "Sequential binding of UV DNA damage binding factor and degradation of the p48 subunit as early events after UV irradiation". Nucleic Acids Research. 30 (11): 2588–98. doi:10.1093/nar/30.11.2588. PMC 117178. PMID 12034848.
  5. ↑ Rapić Otrin V, Kuraoka I, Nardo T, McLenigan M, Eker AP, Stefanini M, Levine AS, Wood RD (June 1998). "Relationship of the xeroderma pigmentosum group E DNA repair defect to the chromatin and DNA binding proteins UV-DDB and replication protein A". Molecular and Cellular Biology. 18 (6): 3182–90. doi:10.1128/mcb.18.6.3182. PMC 108900. PMID 9584159.
  6. ↑ Wittschieben BØ, Iwai S, Wood RD (December 2005). "DDB1-DDB2 (xeroderma pigmentosum group E) protein complex recognizes a cyclobutane pyrimidine dimer, mismatches, apurinic/apyrimidinic sites, and compound lesions in DNA". The Journal of Biological Chemistry. 280 (48): 39982–9. doi:10.1074/jbc.M507854200. PMID 16223728.
  7. ↑ 7.0 7.1 Luijsterburg MS, Goedhart J, Moser J, Kool H, Geverts B, Houtsmuller AB, Mullenders LH, Vermeulen W, van Driel R (August 2007). "Dynamic in vivo interaction of DDB2 E3 ubiquitin ligase with UV-damaged DNA is independent of damage-recognition protein XPC". Journal of Cell Science. 120 (Pt 15): 2706–16. doi:10.1242/jcs.008367. PMID 17635991.
  8. ↑ 8.0 8.1 Pines A, Vrouwe MG, Marteijn JA, Typas D, Luijsterburg MS, Cansoy M, Hensbergen P, Deelder A, de Groot A, Matsumoto S, Sugasawa K, Thoma N, Vermeulen W, Vrieling H, Mullenders L (October 2012). "PARP1 promotes nucleotide excision repair through DDB2 stabilization and recruitment of ALC1". The Journal of Cell Biology. 199 (2): 235–49. doi:10.1083/jcb.201112132. PMC 3471223. PMID 23045548.
  9. ↑ Zhu Q, Battu A, Ray A, Wani G, Qian J, He J, Wang QE, Wani AA (June 2015). "Damaged DNA-binding protein down-regulates epigenetic mark H3K56Ac through histone deacetylase 1 and 2". Mutation Research. 776: 16–23. doi:10.1016/j.mrfmmm.2015.01.005. PMC 5053336. PMID 26255936.
  10. ↑ Zou N, Xie G, Cui T, Srivastava AK, Qu M, Yang L, Wei S, Zheng Y, Wang QE (October 2016). "DDB2 increases radioresistance of NSCLC cells by enhancing DNA damage responses". Tumour Biology. 37 (10): 14183–14191. doi:10.1007/s13277-016-5203-y. PMID 27553023.
  11. ↑ Christmann M, Boisseau C, Kitzinger R, Berac C, Allmann S, Sommer T, Aasland D, Kaina B, Tomicic MT (December 2016). "Adaptive upregulation of DNA repair genes following benzo(a)pyrene diol epoxide protects against cell death at the expense of mutations". Nucleic Acids Research. 44 (22): 10727–10743. doi:10.1093/nar/gkw873. PMC 5159553. PMID 27694624.
  12. ↑ Fantini D, Huang S, Asara JM, Bagchi S, Raychaudhuri P (January 2017). "Chromatin association of XRCC5/6 in the absence of DNA damage depends on the XPE gene product DDB2". Molecular Biology of the Cell. 28 (1): 192–200. doi:10.1091/mbc.E16-08-0573. PMC 5221623. PMID 28035050.

Further reading

External links

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