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Gene Review

XPA  -  xeroderma pigmentosum, complementation...

Homo sapiens

Synonyms: DNA repair protein complementing XP-A cells, XP1, XPAC, Xeroderma pigmentosum group A-complementing protein
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Disease relevance of XPA

  • The xeroderma pigmentosum complementation group A (XP-A) protein, XPA, has recently been expressed in Escherichia coli in a soluble and fully functional form [1].
  • Carriage of at least one variant allele for XPA G23A was associated with decreased risk of endometrial cancer [odds ratio (OR), 0.70; 95% confidence interval (95% CI), 0.53-0.93] [2].
  • In this study, we used synthetic siRNAs targeted to XPA and ERCC1 and compared their effectiveness in sensitising mismatch repair deficient prostate cancer cell lines to cisplatin and mitomycin C [3].
  • We also examined the effect of this XPA-RPA interaction on in vitro simian virus 40 (SV40) DNA replication catalyzed by the crude extract and monopolymerase system [4].
  • We have made a replication-defective adenovirus, AdCMV-FlagXPA(59-114), that expresses a truncated form of XPA encompassing amino acids 59-114 sufficient for binding to the excision repair cross-complementing protein 1 (ERCC1)/xeroderma pigmentosum complementation group F (XPF) nuclease essential for making an incision 5' of the damage [5].

High impact information on XPA

  • Increased susceptibility to ultraviolet-B and carcinogens of mice lacking the DNA excision repair gene XPA [6].
  • We conclude that the XPA-deficient mice strongly mimic the phenotype of humans with xeroderma pigmentosum [6].
  • The XPA protein functions in a pre-incision step, the recognition of DNA damage [6].
  • To permit the functional analysis of the XPA gene in vivo, we have generated XPA-deficient mice by gene targeting in embryonic stem cells [6].
  • RAD14 encodes a highly hydrophilic protein of 247 amino acids containing zinc-finger motifs, and it is similar to the protein encoded by the human XPAC gene that complements XP group A cell lines [7].

Chemical compound and disease context of XPA


Biological context of XPA


Anatomical context of XPA

  • The XPA protein-bound fraction was tested for specific proteins by an in vitro complementation assay with a panel of cell-free extracts from DNA repair-deficient human and rodent cell lines [1].
  • Only the 6 testis tumor cell lines showed significantly lower mean levels of XPA (p = 0.001), XPF (p = 0.001) and ERCC1 (p = 0.004) proteins from the other groups [15].
  • Defective repair of cisplatin-induced DNA damage caused by reduced XPA protein in testicular germ cell tumours [16].
  • Activation of NER in Cr(VI)-treated human fibroblasts or lung epithelial H460 cells was manifested by XPC-dependent binding of the XPA protein to the nuclear matrix, which was also observed in UV light-treated (but not oxidant-stressed) cells [17].
  • Cells cultured from XPA and XPC patients are hypersensitive to UV light, as a result of malfunctioning DNA repair [18].

Associations of XPA with chemical compounds

  • When we stratified the patients according to intravesical Bacillus Calmette-Guerin treatment, we found a significant trend for shorter recurrence-free survival time in patients with variant alleles of XPA or ERCC6 polymorphisms who received Bacillus Calmette-Guerin treatment (log rank test, P = 0.078 and 0.022, respectively) [19].
  • Sequence analyses and genetic evidence suggest that zinc is associated with a C4-type motif, C105-X2-C108-X17-C126-X2-C129, located in the minimal DNA binding region of XPA (M98-F219) [20].
  • Extended X-ray absorption fine structure (EXAFS) spectra collected on the zinc associated minimal DNA-binding domain of XPA (ZnXPA-MBD) show directly, for the first time, that the zinc is coordinated to the sulfur atoms of four cysteine residues with an average Zn-S bond length of 2.34+/-0.01 A [20].
  • A stretch of consecutive glutamic acid residues in XPA was needed for binding to ERCC1 [21].
  • In vivo, the delta E mutant exhibited an intermediate level of complementation of XPA cells and the delta G mutant exhibited little or no complementation [22].

Physical interactions of XPA


Enzymatic interactions of XPA

  • We showed that XPA was a substrate for in vitro phosphorylation by phosphatidylinositol-3-kinase-related kinase family kinases whereas in cells XPA was phosphorylated in an ATR-dependent manner and stimulated by UV irradiation [26].

Regulatory relationships of XPA

  • Furthermore, XPAC inhibited DNA polymerase alpha activity in the presence of RPA but not in RPA's absence [24].
  • BPD is cytotoxic to Cd induced CYP1A1 expressing XPA cells at > 10-fold lower doses than it is to Cd induced CYP1A1 expressing DNA repair normal cells [9].
  • Effect of XPA gene mutations on UV-induced immunostaining of PCNA in fibroblasts from xeroderma pigmentosum group A patients [27].
  • In addition, XPC is necessary to promote a stable binding of XPA to UV-irradiated DNA [28].

Other interactions of XPA

  • These findings identify XPC as the earliest known NER factor in the reaction mechanism, give insight into the order of subsequent NER components, provide evidence for a dual role of XPA, and support a concept of sequential assembly of repair proteins at the site of the damage rather than a preassembled repairosome [29].
  • The absence of RPA, XPA or XPG activities leads to an intermediate level of strand separation [30].
  • We examined the effect of this XPAC-RPA interaction on in vitro simian virus 40 (SV40) DNA replication catalyzed by the monopolymerase system [24].
  • These results suggest that XAB1 is a novel cytoplasmic GTPase involved in nuclear localization of XPA [14].
  • In contrast, depletion of DDB2, XPA, or XPC does not cause activation of DNA damage checkpoints, indicating that defects in NER are not involved [31].

Analytical, diagnostic and therapeutic context of XPA


  1. Formation of a ternary complex by human XPA, ERCC1, and ERCC4(XPF) excision repair proteins. Park, C.H., Sancar, A. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  2. Interindividual variation in nucleotide excision repair genes and risk of endometrial cancer. Weiss, J.M., Weiss, N.S., Ulrich, C.M., Doherty, J.A., Voigt, L.F., Chen, C. Cancer Epidemiol. Biomarkers Prev. (2005) [Pubmed]
  3. XPA versus ERCC1 as chemosensitising agents to cisplatin and mitomycin C in prostate cancer cells: role of ERCC1 in homologous recombination repair. Cummings, M., Higginbottom, K., McGurk, C.J., Wong, O.G., Köberle, B., Oliver, R.T., Masters, J.R. Biochem. Pharmacol. (2006) [Pubmed]
  4. Functional studies on the interaction between human replication protein A and Xeroderma pigmentosum group A complementing protein (XPA). Lee, B.E., Sung, J.W., Kim, D.K., Lee, J.R., Kim, N.D., Kang, S.W., Kim, D.K. Mol. Cells (1999) [Pubmed]
  5. A truncated human xeroderma pigmentosum complementation group A protein expressed from an adenovirus sensitizes human tumor cells to ultraviolet light and cisplatin. Rosenberg, E., Taher, M.M., Kuemmerle, N.B., Farnsworth, J., Valerie, K. Cancer Res. (2001) [Pubmed]
  6. Increased susceptibility to ultraviolet-B and carcinogens of mice lacking the DNA excision repair gene XPA. de Vries, A., van Oostrom, C.T., Hofhuis, F.M., Dortant, P.M., Berg, R.J., de Gruijl, F.R., Wester, P.W., van Kreijl, C.F., Capel, P.J., van Steeg, H. Nature (1995) [Pubmed]
  7. Yeast RAD14 and human xeroderma pigmentosum group A DNA-repair genes encode homologous proteins. Bankmann, M., Prakash, L., Prakash, S. Nature (1992) [Pubmed]
  8. The Involvement of Ataxia-telangiectasia Mutated Protein Activation in Nucleotide Excision Repair-facilitated Cell Survival with Cisplatin Treatment. Colton, S.L., Xu, X.S., Wang, Y.A., Wang, G. J. Biol. Chem. (2006) [Pubmed]
  9. Expression of human cytochrome P450 1A1 in DNA repair deficient and proficient human fibroblasts stably transformed with an inducible expression vector. States, J.C., Quan, T., Hines, R.N., Novak, R.F., Runge-Morris, M. Carcinogenesis (1993) [Pubmed]
  10. Development of new EBV-based vectors for stable expression of small interfering RNA to mimick human syndromes: application to NER gene silencing. Biard, D.S., Despras, E., Sarasin, A., Angulo, J.F. Mol. Cancer Res. (2005) [Pubmed]
  11. DNA double-strand breaks induced in normal human cells during the repair of ultraviolet light damage. Bradley, M.O., Taylor, V.I. Proc. Natl. Acad. Sci. U.S.A. (1981) [Pubmed]
  12. Absence of DNA repair deficiency in the confirmed heterozygotes of xeroderma pigmentosum group A. Moriwaki, S., Nishigori, C., Teramoto, T., Tanaka, T., Kore-eda, S., Takebe, H., Imamura, S. J. Invest. Dermatol. (1993) [Pubmed]
  13. ERCC1 mutations in UV-sensitive Chinese hamster ovary (CHO) cell lines. Hayashi, T., Takao, M., Tanaka, K., Yasui, A. Mutat. Res. (1998) [Pubmed]
  14. A novel cytoplasmic GTPase XAB1 interacts with DNA repair protein XPA. Nitta, M., Saijo, M., Kodo, N., Matsuda, T., Nakatsu, Y., Tamai, H., Tanaka, K. Nucleic Acids Res. (2000) [Pubmed]
  15. Reduced levels of XPA, ERCC1 and XPF DNA repair proteins in testis tumor cell lines. Welsh, C., Day, R., McGurk, C., Masters, J.R., Wood, R.D., Köberle, B. Int. J. Cancer (2004) [Pubmed]
  16. Defective repair of cisplatin-induced DNA damage caused by reduced XPA protein in testicular germ cell tumours. Köberle, B., Masters, J.R., Hartley, J.A., Wood, R.D. Curr. Biol. (1999) [Pubmed]
  17. Human nucleotide excision repair efficiently removes chromium-DNA phosphate adducts and protects cells against chromate toxicity. Reynolds, M., Peterson, E., Quievryn, G., Zhitkovich, A. J. Biol. Chem. (2004) [Pubmed]
  18. Complementation of the DNA repair deficiency in human xeroderma pigmentosum group a and C cells by recombinant adenovirus-mediated gene transfer. Muotri, A.R., Marchetto, M.C., Zerbini, L.F., Libermann, T.A., Ventura, A.M., Sarasin, A., Menck, C.F. Hum. Gene Ther. (2002) [Pubmed]
  19. Nucleotide excision repair gene polymorphisms and recurrence after treatment for superficial bladder cancer. Gu, J., Zhao, H., Dinney, C.P., Zhu, Y., Leibovici, D., Bermejo, C.E., Grossman, H.B., Wu, X. Clin. Cancer Res. (2005) [Pubmed]
  20. Human nucleotide excision repair protein XPA: extended X-ray absorption fine-structure evidence for a metal-binding domain. Hess, N.J., Buchko, G.W., Conradson, S.D., Espinosa, F.J., Ni, S., Thrall, B.D., Kennedy, M.A. Protein Sci. (1998) [Pubmed]
  21. Enhancement of damage-specific DNA binding of XPA by interaction with the ERCC1 DNA repair protein. Nagai, A., Saijo, M., Kuraoka, I., Matsuda, T., Kodo, N., Nakatsu, Y., Mimaki, T., Mino, M., Biggerstaff, M., Wood, R.D. Biochem. Biophys. Res. Commun. (1995) [Pubmed]
  22. Mutations in XPA that prevent association with ERCC1 are defective in nucleotide excision repair. Li, L., Peterson, C.A., Lu, X., Legerski, R.J. Mol. Cell. Biol. (1995) [Pubmed]
  23. Biochemical analysis of the damage recognition process in nucleotide excision repair. You, J.S., Wang, M., Lee, S.H. J. Biol. Chem. (2003) [Pubmed]
  24. Human xeroderma pigmentosum group A protein interacts with human replication protein A and inhibits DNA replication. Lee, S.H., Kim, D.K., Drissi, R. J. Biol. Chem. (1995) [Pubmed]
  25. XAB2, a novel tetratricopeptide repeat protein involved in transcription-coupled DNA repair and transcription. Nakatsu, Y., Asahina, H., Citterio, E., Rademakers, S., Vermeulen, W., Kamiuchi, S., Yeo, J.P., Khaw, M.C., Saijo, M., Kodo, N., Matsuda, T., Hoeijmakers, J.H., Tanaka, K. J. Biol. Chem. (2000) [Pubmed]
  26. Phosphorylation of nucleotide excision repair factor xeroderma pigmentosum group A by ataxia telangiectasia mutated and Rad3-related-dependent checkpoint pathway promotes cell survival in response to UV irradiation. Wu, X., Shell, S.M., Yang, Z., Zou, Y. Cancer Res. (2006) [Pubmed]
  27. Effect of XPA gene mutations on UV-induced immunostaining of PCNA in fibroblasts from xeroderma pigmentosum group A patients. Miura, M., Sasaki, T. Mutat. Res. (1996) [Pubmed]
  28. Interactions of the transcription/DNA repair factor TFIIH and XP repair proteins with DNA lesions in a cell-free repair assay. Li, R.Y., Calsou, P., Jones, C.J., Salles, B. J. Mol. Biol. (1998) [Pubmed]
  29. Sequential assembly of the nucleotide excision repair factors in vivo. Volker, M., Moné, M.J., Karmakar, P., van Hoffen, A., Schul, W., Vermeulen, W., Hoeijmakers, J.H., van Driel, R., van Zeeland, A.A., Mullenders, L.H. Mol. Cell (2001) [Pubmed]
  30. Mechanism of open complex and dual incision formation by human nucleotide excision repair factors. Evans, E., Moggs, J.G., Hwang, J.R., Egly, J.M., Wood, R.D. EMBO J. (1997) [Pubmed]
  31. DDB1 Maintains Genome Integrity through Regulation of Cdt1. Lovejoy, C.A., Lock, K., Yenamandra, A., Cortez, D. Mol. Cell. Biol. (2006) [Pubmed]
  32. Genomic polymorphisms provide prognostic information in intermediate-risk acute myeloblastic leukemia. Monzo, M., Brunet, S., Urbano-Ispizua, A., Navarro, A., Perea, G., Esteve, J., Artells, R., Granell, M., Berlanga, J., Ribera, J.M., Bueno, J., Llorente, A., Guardia, R., Tormo, M., Torres, P., Nomdedéu, J.F., Montserrat, E., Sierra, J. Blood (2006) [Pubmed]
  33. Regulation of DNA repair gene expression in human cancer cell lines. McGurk, C.J., Cummings, M., Köberle, B., Hartley, J.A., Oliver, R.T., Masters, J.R. J. Cell. Biochem. (2006) [Pubmed]
  34. Xeroderma pigmentosum group A protein loads as a separate factor onto DNA lesions. Rademakers, S., Volker, M., Hoogstraten, D., Nigg, A.L., Moné, M.J., Van Zeeland, A.A., Hoeijmakers, J.H., Houtsmuller, A.B., Vermeulen, W. Mol. Cell. Biol. (2003) [Pubmed]
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