xeroderma pigmentosum group a protein


Summary: A ZINC FINGER MOTIF protein that recognizes and interacts with damaged DNA. It is a DNA-binding protein that plays an essential role in NUCLEOTIDE EXCISION REPAIR. Mutations in this protein are associated with the most severe form of XERODERMA PIGMENTOSUM.

Top Publications

  1. Soufir N, Ged C, Bourillon A, Austerlitz F, Chemin C, Stary A, et al. A prevalent mutation with founder effect in xeroderma pigmentosum group C from north Africa. J Invest Dermatol. 2010;130:1537-42 pubmed publisher
    ..As the (p.Val548AlafsX25) XPC mutation is responsible for a huge proportion of XP cases, our data imply an obvious simplification of XP molecular diagnosis, at least in North Africa. ..
  2. Orelli B, McClendon T, Tsodikov O, Ellenberger T, Niedernhofer L, SCHARER O. The XPA-binding domain of ERCC1 is required for nucleotide excision repair but not other DNA repair pathways. J Biol Chem. 2010;285:3705-12 pubmed publisher
    ..We discuss the impact of these findings for understanding how ERCC1 contributes to resistance of tumor cells to therapeutic agents such as cisplatin. ..
  3. Andrew A, Karagas M, Hamilton J. Decreased DNA repair gene expression among individuals exposed to arsenic in United States drinking water. Int J Cancer. 2003;104:263-8 pubmed
    ..Although our findings need verification in a larger study group, they are consistent with the hypothesis that inhibition of DNA repair capacity is a potential mechanism for the co-carcinogenic activity of arsenic...
  4. de Boer J, Andressoo J, de Wit J, Huijmans J, Beems R, van Steeg H, et al. Premature aging in mice deficient in DNA repair and transcription. Science. 2002;296:1276-9 pubmed
    ..We hypothesize that aging in TTD mice is caused by unrepaired DNA damage that compromises transcription, leading to functional inactivation of critical genes and enhanced apoptosis...
  5. de Laat W, Jaspers N, Hoeijmakers J. Molecular mechanism of nucleotide excision repair. Genes Dev. 1999;13:768-85 pubmed
  6. Hermanson Miller I, Turchi J. Strand-specific binding of RPA and XPA to damaged duplex DNA. Biochemistry. 2002;41:2402-8 pubmed
    ..Two proteins, xeroderma pigmentosum group A protein (XPA) and replication protein A (RPA), have been implicated in the role of DNA damage recognition ..
  7. Reardon J, Sancar A. Repair of DNA-polypeptide crosslinks by human excision nuclease. Proc Natl Acad Sci U S A. 2006;103:4056-61 pubmed
    ..Our data suggest that, if coupled with proteolytic degradation of the crosslinked protein, the human excision nuclease may be the major enzyme system for eliminating protein-DNA crosslinks from the genome. ..
  8. Krasikova Y, Rechkunova N, Maltseva E, Petruseva I, Silnikov V, Zatsepin T, et al. Interaction of nucleotide excision repair factors XPC-HR23B, XPA, and RPA with damaged DNA. Biochemistry (Mosc). 2008;73:886-96 pubmed
    ..The data are in agreement with the cooperative binding model of nucleotide excision repair factors participating in pre-incision complex formation with DNA duplexes bearing damages. ..
  9. Wakasugi M, Kasashima H, Fukase Y, Imura M, Imai R, Yamada S, et al. Physical and functional interaction between DDB and XPA in nucleotide excision repair. Nucleic Acids Res. 2009;37:516-25 pubmed publisher
    ..These results suggest that the physical interaction between DDB and XPA plays an important role in the DDB-mediated NER reaction. ..

More Information


  1. Kölgen W, van Steeg H, van der Horst G, Hoeijmakers J, van Vloten W, de Gruijl F, et al. Association of transcription-coupled repair but not global genome repair with ultraviolet-B-induced Langerhans cell depletion and local immunosuppression. J Invest Dermatol. 2003;121:751-6 pubmed
    ..In combination with earlier experiments, it can be concluded that Langerhans cell disappearance is related to ultraviolet-B-induced local but not to systemic immunosuppression. ..
  2. Hirai Y, Kodama Y, Moriwaki S, Noda A, Cullings H, MacPhee D, et al. Heterozygous individuals bearing a founder mutation in the XPA DNA repair gene comprise nearly 1% of the Japanese population. Mutat Res. 2006;601:171-8 pubmed
    ..88%. This rate, if representative, implies that there are about 1 million carriers of the XPA founder mutation in the Japanese population. Thus, investigation of their cancer risk may be warranted...
  3. Tapias A, Auriol J, Forget D, Enzlin J, SCHARER O, Coin F, et al. Ordered conformational changes in damaged DNA induced by nucleotide excision repair factors. J Biol Chem. 2004;279:19074-83 pubmed
    ..XPG and XPF/ERCC1 endonucleases then cut the damaged DNA at the limit of the opened structure that was previously "labeled" by the positioning of XPC/HR23B and TFIIH. ..
  4. Mer G, Bochkarev A, Gupta R, Bochkareva E, Frappier L, Ingles C, et al. Structural basis for the recognition of DNA repair proteins UNG2, XPA, and RAD52 by replication factor RPA. Cell. 2000;103:449-56 pubmed
    ..Our findings support a hand-off model for the assembly and coordination of different components of the DNA repair machinery. ..
  5. Wakasugi M, Sancar A. Order of assembly of human DNA repair excision nuclease. J Biol Chem. 1999;274:18759-68 pubmed
    ..We conclude that RPA and XPA are the initial damage sensing factors of human excision nuclease. ..
  6. Solimando L, Luijsterburg M, Vecchio L, Vermeulen W, van Driel R, Fakan S. Spatial organization of nucleotide excision repair proteins after UV-induced DNA damage in the human cell nucleus. J Cell Sci. 2009;122:83-91 pubmed publisher
    ..Our results offer novel insight into the dynamic spatial organization of DNA repair in the human cell nucleus. ..
  7. Köberle B, Roginskaya V, Wood R. XPA protein as a limiting factor for nucleotide excision repair and UV sensitivity in human cells. DNA Repair (Amst). 2006;5:641-8 pubmed
    ..To inhibit NER, it may be more effective to interfere with XPA protein function, rather than reducing XPA protein levels. ..
  8. Barakat K, Torin Huzil J, Luchko T, Jordheim L, Dumontet C, Tuszynski J. Characterization of an inhibitory dynamic pharmacophore for the ERCC1-XPA interaction using a combined molecular dynamics and virtual screening approach. J Mol Graph Model. 2009;28:113-30 pubmed publisher
    ..Lowest energy poses from the two different methods were then used to construct a pharmacophore model, which was then validated by comparison to UCN-01, a weak inhibitor of ERCC1 mediated nucleotide excision. ..
  9. Nakane H, Takeuchi S, Yuba S, Saijo M, Nakatsu Y, Murai H, et al. High incidence of ultraviolet-B-or chemical-carcinogen-induced skin tumours in mice lacking the xeroderma pigmentosum group A gene. Nature. 1995;377:165-8 pubmed
    ..The XPA-deficient mice may provide a good in vivo model to study the high incidence of skin carcinogenesis in group A XP patients. ..
  10. Schwarz A, Maeda A, Kernebeck K, van Steeg H, Beissert S, Schwarz T. Prevention of UV radiation-induced immunosuppression by IL-12 is dependent on DNA repair. J Exp Med. 2005;201:173-9 pubmed
    ..These data identify a new mechanism by which IL-12 can restore immune responses and also demonstrate a link between DNA repair and the prevention of UV-induced immunosuppression by IL-12. ..
  11. Hoogstraten D, Bergink S, Ng J, Verbiest V, Luijsterburg M, Geverts B, et al. Versatile DNA damage detection by the global genome nucleotide excision repair protein XPC. J Cell Sci. 2008;121:2850-9 pubmed publisher
  12. Bomgarden R, Lupardus P, Soni D, Yee M, Ford J, Cimprich K. Opposing effects of the UV lesion repair protein XPA and UV bypass polymerase eta on ATR checkpoint signaling. EMBO J. 2006;25:2605-14 pubmed
    ..Taken together, these results suggest that lesion bypass and not lesion repair may raise the level of UV damage that can be tolerated before checkpoint activation, and that XPA plays a critical role in this activation. ..
  13. Sidwell R, Sandison A, Wing J, Fawcett H, Seet J, Fisher C, et al. A novel mutation in the XPA gene associated with unusually mild clinical features in a patient who developed a spindle cell melanoma. Br J Dermatol. 2006;155:81-8 pubmed
    ..These complementation groups correspond to different proteins involved in the NER process. XP-A classically includes some of the most severely affected patients...
  14. van der Pluijm I, Garinis G, Brandt R, Gorgels T, Wijnhoven S, Diderich K, et al. Impaired genome maintenance suppresses the growth hormone--insulin-like growth factor 1 axis in mice with Cockayne syndrome. PLoS Biol. 2007;5:e2 pubmed
    ..Importantly, wild-type mice exposed to a low dose of chronic genotoxic stress recapitulated this response, thereby pointing to a novel link between genome instability and the age-related decline of the somatotroph axis. ..
  15. Astin J, O Neil N, Kuwabara P. Nucleotide excision repair and the degradation of RNA pol II by the Caenorhabditis elegans XPA and Rsp5 orthologues, RAD-3 and WWP-1. DNA Repair (Amst). 2008;7:267-80 pubmed
    ..The absence of wwp-1 by itself does not cause sensitivity to UV irradiation, but it acts synergistically with a mutation in xpa-1 to enhance UV hypersensitivity. ..
  16. Gilljam K, Müller R, Liabakk N, Otterlei M. Nucleotide excision repair is associated with the replisome and its efficiency depends on a direct interaction between XPA and PCNA. PLoS ONE. 2012;7:e49199 pubmed publisher
    ..Altogether, our results suggest a presence of the NER complex in the vicinity of the replisome and a novel role of NER in post-replicative repair. ..
  17. Kang T, Sancar A. Circadian regulation of DNA excision repair: implications for chrono-chemotherapy. Cell Cycle. 2009;8:1665-7 pubmed
    ..Here we review the significance of the connection linking the circadian clock with nucleotide excision repair and discuss potential implications for chemotherapy. ..
  18. Takahashi Y, Endo Y, Sugiyama Y, Inoue S, Iijima M, Tomita Y, et al. XPA gene mutations resulting in subtle truncation of protein in xeroderma pigmentosum group A patients with mild skin symptoms. J Invest Dermatol. 2010;130:2481-8 pubmed publisher
  19. Cleaver J, McDowell M, Jones C, Wood R, Karentz D. Mutation and expression of the XPA gene in revertants and hybrids of a xeroderma pigmentosum cell line. Somat Cell Mol Genet. 1994;20:327-37 pubmed
  20. Park C, Sancar A. Formation of a ternary complex by human XPA, ERCC1, and ERCC4(XPF) excision repair proteins. Proc Natl Acad Sci U S A. 1994;91:5017-21 pubmed
    ..We conclude that the XPA damage recognition protein makes a ternary complex with the ERCC1/ERCC4(XPF) heterodimer with a potential nuclease function. ..
  21. Sugasawa K, Ng J, Masutani C, Iwai S, van der Spek P, Eker A, et al. Xeroderma pigmentosum group C protein complex is the initiator of global genome nucleotide excision repair. Mol Cell. 1998;2:223-32 pubmed
    ..After this subpathway-specific initial lesion detection, XPA may function as a common damage verifier and adaptor to the core of the NER apparatus. ..
  22. Rademakers S, Volker M, Hoogstraten D, Nigg A, Moné M, Van Zeeland A, et al. Xeroderma pigmentosum group A protein loads as a separate factor onto DNA lesions. Mol Cell Biol. 2003;23:5755-67 pubmed
    ..NER involves the concerted action of more than 25 polypeptides in a coordinated fashion. The xeroderma pigmentosum group A protein (XPA) has been suggested to function as a central organizer and damage verifier in NER...
  23. Wang Q, Zhu Q, Wani G, El Mahdy M, Li J, Wani A. DNA repair factor XPC is modified by SUMO-1 and ubiquitin following UV irradiation. Nucleic Acids Res. 2005;33:4023-34 pubmed
    ..Our results also suggest that at least one function of UV-induced XPC sumoylation is related to the stabilization of XPC protein. ..
  24. Shell S, Li Z, Shkriabai N, Kvaratskhelia M, Brosey C, Serrano M, et al. Checkpoint kinase ATR promotes nucleotide excision repair of UV-induced DNA damage via physical interaction with xeroderma pigmentosum group A. J Biol Chem. 2009;284:24213-22 pubmed publisher
    ..Taken together, our results suggest that the ATR-XPA interaction mediated by the helix-turn-helix motif of XPA plays an important role in DNA-damage responses to promote cell survival and genomic stability after UV irradiation. ..
  25. Nouspikel T. DNA repair in mammalian cells : Nucleotide excision repair: variations on versatility. Cell Mol Life Sci. 2009;66:994-1009 pubmed publisher
    ..It concludes by discussing several currently unresolved issues, relating either to the cause of the above diseases or to the mechanistic details of the various NER subpathways and of their regulation. (Part of a Multi-author Review). ..
  26. Araújo S, Nigg E, Wood R. Strong functional interactions of TFIIH with XPC and XPG in human DNA nucleotide excision repair, without a preassembled repairosome. Mol Cell Biol. 2001;21:2281-91 pubmed
    ..A panel of antibodies was used to estimate that there are on the order of 10(5) molecules of each core NER factor per HeLa cell. ..
  27. Melis J, Wijnhoven S, Beems R, Roodbergen M, van den Berg J, Moon H, et al. Mouse models for xeroderma pigmentosum group A and group C show divergent cancer phenotypes. Cancer Res. 2008;68:1347-53 pubmed publisher
  28. You J, Wang M, Lee S. Biochemical analysis of the damage recognition process in nucleotide excision repair. J Biol Chem. 2003;278:7476-85 pubmed
    ..XPA and RPA, once forming a complex at the damage site, would likely work with TFIIH, XPG, and ERCC1-XPF for dual incision. ..
  29. Thoma B, Wakasugi M, Christensen J, Reddy M, Vasquez K. Human XPC-hHR23B interacts with XPA-RPA in the recognition of triplex-directed psoralen DNA interstrand crosslinks. Nucleic Acids Res. 2005;33:2993-3001 pubmed
  30. Butkiewicz D, Popanda O, Risch A, Edler L, Dienemann H, Schulz V, et al. Association between the risk for lung adenocarcinoma and a (-4) G-to-A polymorphism in the XPA gene. Cancer Epidemiol Biomarkers Prev. 2004;13:2242-6 pubmed
    ..The underlying mechanisms as to why AA homozygotes are predisposed to lung adenocarcinoma and which specific carcinogens are involved remains to be determined. ..
  31. Li L, Lu X, Peterson C, Legerski R. An interaction between the DNA repair factor XPA and replication protein A appears essential for nucleotide excision repair. Mol Cell Biol. 1995;15:5396-402 pubmed
    ..Taken together, these results indicate that the interaction between XPA and RPA is required for NER but that only the interaction with RPA-70 is essential. ..
  32. Shimamoto T, Tanimura T, Yoneda Y, Kobayakawa Y, Sugasawa K, Hanaoka F, et al. Expression and functional analyses of the Dxpa gene, the Drosophila homolog of the human excision repair gene XPA. J Biol Chem. 1995;270:22452-9 pubmed
  33. Cleaver J. Cancer in xeroderma pigmentosum and related disorders of DNA repair. Nat Rev Cancer. 2005;5:564-73 pubmed
    ..Complex clinical phenotypes might therefore result from unanticipated effects on other genes and proteins...
  34. Fishelevich R, Zhao Y, Tuchinda P, Liu H, Nakazono A, Tammaro A, et al. Imiquimod-induced TLR7 signaling enhances repair of DNA damage induced by ultraviolet light in bone marrow-derived cells. J Immunol. 2011;187:1664-73 pubmed publisher
    ..This property is likely to be an important mechanism for its anticancer effects because it protects cutaneous APC from the deleterious effects of UVL. ..
  35. Coin F, Oksenych V, Mocquet V, Groh S, Blattner C, Egly J. Nucleotide excision repair driven by the dissociation of CAK from TFIIH. Mol Cell. 2008;31:9-20 pubmed publisher
    ..Our findings demonstrate that the composition of TFIIH is dynamic to adapt its engagement in distinct cellular processes. ..
  36. Köberle B, Roginskaya V, Zima K, Masters J, Wood R. Elevation of XPA protein level in testis tumor cells without increasing resistance to cisplatin or UV radiation. Mol Carcinog. 2008;47:580-6 pubmed publisher
    ..The relative sensitivity of testis tumor cells to cisplatin, UV radiation, and other DNA damaging agents is likely related not to NER capacity, but to other factors such as the integrity of the p53 pathway in these cells. ..
  37. Fischer E, Scrima A, Böhm K, Matsumoto S, Lingaraju G, Faty M, et al. The molecular basis of CRL4DDB2/CSA ubiquitin ligase architecture, targeting, and activation. Cell. 2011;147:1024-39 pubmed publisher
    ..Our data support a general mechanism of ligase activation, which is induced by CSN displacement from CRL4(DCAF) on substrate binding to the DCAF. ..
  38. Wakasugi M, Kawashima A, Morioka H, Linn S, Sancar A, Mori T, et al. DDB accumulates at DNA damage sites immediately after UV irradiation and directly stimulates nucleotide excision repair. J Biol Chem. 2002;277:1637-40 pubmed
    ..These results suggest that DDB can rapidly translocate to the damaged DNA sites independent of functional XPA and XPC proteins and directly enhance the excision reaction by core repair factors. ..
  39. Guillonneau F, Guieysse A, Nocentini S, Giovannangeli C, Praseuth D. Psoralen interstrand cross-link repair is specifically altered by an adjacent triple-stranded structure. Nucleic Acids Res. 2004;32:1143-53 pubmed
    ..These data characterize triplex-induced modulation of ICL repair pathways at specific steps, which might have implications for the controlled induction of targeted genomic modifications and for the associated cellular responses. ..
  40. Kuru S, Yasuma M, Sakai M, Konagaya M, Moriwaki S. [Siblings with xeroderma pigmentosum group A showing mild cutaneous and various neurological manifestations]. Rinsho Shinkeigaku. 2006;46:134-9 pubmed
    ..It is suggested that transcription-coupled repair is dominantly affected with relative sparing of global genome repair in these siblings...
  41. Kang T, Reardon J, Kemp M, Sancar A. Circadian oscillation of nucleotide excision repair in mammalian brain. Proc Natl Acad Sci U S A. 2009;106:2864-7 pubmed publisher
    ..The circadian oscillation of the repair capacity is caused at least in part by the circadian oscillation of the xeroderma pigmentosum A DNA damage recognition protein. ..
  42. Krasikova Y, Rechkunova N, Maltseva E, Petruseva I, Lavrik O. Localization of xeroderma pigmentosum group A protein and replication protein A on damaged DNA in nucleotide excision repair. Nucleic Acids Res. 2010;38:8083-94 pubmed publisher
    The interaction of xeroderma pigmentosum group A protein (XPA) and replication protein A (RPA) with damaged DNA in nucleotide excision repair (NER) was studied using model dsDNA and bubble-DNA structure with 5-{3-[6-(carboxyamido-..
  43. Park C, Mu D, Reardon J, Sancar A. The general transcription-repair factor TFIIH is recruited to the excision repair complex by the XPA protein independent of the TFIIE transcription factor. J Biol Chem. 1995;270:4896-902 pubmed
    ..This latter interaction has no apparent role in general excision repair but may be relevant in the transcription-coupled repair reaction. ..
  44. Kang T, Lindsey Boltz L, Reardon J, Sancar A. Circadian control of XPA and excision repair of cisplatin-DNA damage by cryptochrome and HERC2 ubiquitin ligase. Proc Natl Acad Sci U S A. 2010;107:4890-5 pubmed publisher
    ..These findings may be used as a guide for timing of cisplatin chemotherapy. ..
  45. Kang T, Reardon J, Sancar A. Regulation of nucleotide excision repair activity by transcriptional and post-transcriptional control of the XPA protein. Nucleic Acids Res. 2011;39:3176-87 pubmed publisher
    ..Collectively, the data reveal that XPA is a limiting factor in excision repair and that its level is coordinately regulated by the circadian clock, the ubiquitin-proteasome system and DNA damage. ..
  46. Messaoud O, Rekaya M, Ouragini H, Benfadhel S, Azaiez H, Kefi R, et al. Severe phenotypes in two Tunisian families with novel XPA mutations: evidence for a correlation between mutation location and disease severity. Arch Dermatol Res. 2012;304:171-6 pubmed publisher
    ..Despite a relatively homogenous mutational spectrum, mutational heterogeneity for rare cases is observed because of the high rate of consanguinity. ..
  47. Li R, Calsou P, Jones C, Salles B. Interactions of the transcription/DNA repair factor TFIIH and XP repair proteins with DNA lesions in a cell-free repair assay. J Mol Biol. 1998;281:211-8 pubmed
    ..Finally, the co-binding of XPA and TFIIH to DNA damage is correlated to a dose-dependent titration of TFIIH and not XPA from the free protein fraction. ..
  48. Wu X, Zhao H, Wei Q, Amos C, Zhang K, Guo Z, et al. XPA polymorphism associated with reduced lung cancer risk and a modulating effect on nucleotide excision repair capacity. Carcinogenesis. 2003;24:505-9 pubmed
    ..Our data suggest that the XPA 5' non-coding region polymorphism modulates NER capacity and is associated with decreased lung cancer risk, especially in the presence of exposure to tobacco carcinogens. ..
  49. Popanda O, Schattenberg T, Phong C, Butkiewicz D, Risch A, Edler L, et al. Specific combinations of DNA repair gene variants and increased risk for non-small cell lung cancer. Carcinogenesis. 2004;25:2433-41 pubmed
    ..Analyses of additional DNA repair gene interactions in larger population-based studies are warranted for identification of high-risk subjects. ..
  50. Nakatsu Y, Asahina H, Citterio E, Rademakers S, Vermeulen W, Kamiuchi S, et al. XAB2, a novel tetratricopeptide repeat protein involved in transcription-coupled DNA repair and transcription. J Biol Chem. 2000;275:34931-7 pubmed
    ..These results indicate that XAB2 is a novel component involved in transcription-coupled repair and transcription. ..
  51. Cummings M, Higginbottom K, McGurk C, Wong O, Köberle B, Oliver R, et al. XPA versus ERCC1 as chemosensitising agents to cisplatin and mitomycin C in prostate cancer cells: role of ERCC1 in homologous recombination repair. Biochem Pharmacol. 2006;72:166-75 pubmed
    ..These results indicate that ERCC1 is a broader therapeutic target than XPA with which to sensitise cancer cells to chemotherapy because of its additional role in recombination repair. ..
  52. Park J, Park S, Choi J, Lee S, Jeon H, Cha S, et al. Polymorphisms of the DNA repair gene xeroderma pigmentosum group A and risk of primary lung cancer. Cancer Epidemiol Biomarkers Prev. 2002;11:993-7 pubmed
    ..51; 95% CI, 0.30-0.86), younger individuals (OR, 0.39; 95% CI, 0.19-0.80), and current smokers (OR, 0.46; 95% CI, 0.25-0.83). These results suggest that the XPA A23G polymorphism contributes to genetic susceptibility for lung cancer. ..
  53. Dzagnidze A, Katsarava Z, Makhalova J, Liedert B, Yoon M, Kaube H, et al. Repair capacity for platinum-DNA adducts determines the severity of cisplatin-induced peripheral neuropathy. J Neurosci. 2007;27:9451-7 pubmed