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XPC  -  xeroderma pigmentosum, complementation...

Homo sapiens

Synonyms: DNA repair protein complementing XP-C cells, RAD4, XP3, XPCC, Xeroderma pigmentosum group C-complementing protein, ...
 
 
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Disease relevance of XPC

  • Our observations suggest that XPC-HR23B may participate in BER of G/T mismatches, thereby contributing to the suppression of spontaneous mutations that may be one of the contributory factors for the promotion of carcinogenesis in xeroderma pigmentosum genetic complementation group C patients [1].
  • Our data suggest that interindividual variation in XPA and XPC influences a woman's risk of endometrial cancer [2].
  • Combinations of polymorphisms in XPD, XPC and XPA in relation to risk of lung cancer [3].
  • Moreover, studies of cells deficient in XPC or in the genes implicated in Cockayne syndrome (CSA and CSB) indicated that the drug sensitivity is specifically dependent on the transcription-coupled pathway of NER [4].
  • One hundred percent of XPC-/- mice develop multiple spontaneous lung tumors with a minority progressing to non-small cell lung adenocarcinoma, occasionally with metastasis to adjacent lymph nodes [5].
 

Psychiatry related information on XPC

 

High impact information on XPC

  • Our results strongly suggest that ubiquitylation plays a critical role in the transfer of the UV-induced lesion from UV-DDB to XPC [7].
  • The xeroderma pigmentosum group C (XPC) protein complex plays a key role in recognizing DNA damage throughout the genome for mammalian nucleotide excision repair (NER) [7].
  • Here we report the results of a characterization of XPCC at the nucleotide level in five XP-C cell lines [8].
  • We have isolated a mouse homologue of the human gene for XP group C and generated XPC-deficient mice by using embryonic stem cell technology [9].
  • Interestingly, NER-type DNA damage further stabilizes XPC and thereby enhances repair [10].
 

Chemical compound and disease context of XPC

 

Biological context of XPC

  • These data support a mechanism in which TFIIH-associated helicase activity and XPC protein catalyze initial formation of the key open intermediate, with full extension to the cleavage sites promoted by the other core nucleotide excision repair factors [16].
  • The XPC-HR23B complex recognizes various helix-distorting lesions in DNA and initiates global genome nucleotide excision repair [1].
  • Here, we show that XPC plays an unexpected and multifaceted role in cell protection from oxidative DNA damage [17].
  • Before the excision reaction, DNA damage is recognized by a complex originally thought to contain the XP group C responsible gene product (XPC) and the human homologue of Rad23 B (HR23B) [18].
  • These results suggest that the NER process may prevent the cisplatin treatment-induced apoptosis by activating the ATM protein, and that the presence of the XPC protein is essential for recruiting the ATM protein to the DNA template [19].
 

Anatomical context of XPC

  • XP-C primary keratinocytes and fibroblasts are hypersensitive to the killing effects of DNA-oxidizing agents and this effect is reverted by expression of wild-type XPC [17].
  • Upon oxidant exposure, XP-C primary keratinocytes and fibroblasts accumulate 8,5'-cyclopurine 2'-deoxynucleosides in their DNA, indicating that XPC is involved in their removal [17].
  • Similarly, rapid recruitment of XPC to DNA damage in situ was also impaired in both cell lines [20].
  • 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 [21].
  • Cells cultured from XPA and XPC patients are hypersensitive to UV light, as a result of malfunctioning DNA repair [22].
 

Associations of XPC with chemical compounds

 

Physical interactions of XPC

  • XPC physically interacted with XPA, but failed to stabilize the XPA-damaged DNA complex [27].
  • The XPC protein is complexed with HHR23B, one of the two human homologs of the yeast NER protein, RAD23 (Masutani at al. (1994) EMBO J. 8, 1831-1843) [24].
  • Flexibility and plasticity of human centrin 2 binding to the xeroderma pigmentosum group C protein (XPC) from nuclear excision repair [28].
  • The C-terminal domain of centrin (C-HsCen2) binds strongly a peptide from the XPC protein (P1-XPC: N(847)-R(863)) [28].
  • Structure of the XPC binding domain of hHR23A reveals hydrophobic patches for protein interaction [29].
 

Regulatory relationships of XPC

  • In a reconstituted repair system, hHR23B stimulated XPC activity tenfold [30].
  • In addition, XPC is necessary to promote a stable binding of XPA to UV-irradiated DNA [31].
  • In contrast, three XPC cell lines which show intermediate UV-induced repair replication and UV sensitivity were sensitized little (in one case) or not at all (in two cases) to UV by postirradiation inhibition of the alpha polymerase [32].
 

Other interactions of XPC

  • 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 [33].
  • In vitro experiments suggest that the mechanism involved is a combination of increased loading and turnover of OGG1 by XPC-HR23B complex [17].
  • Strong functional interactions of TFIIH with XPC and XPG in human DNA nucleotide excision repair, without a preassembled repairosome [34].
  • Thus, those findings suggest that the XPC-CEN2 interaction may reflect coupling of cell division and NER [18].
  • It also showed that a functional XPC protein was required for the association of the ATM protein to genomic DNA [19].
 

Analytical, diagnostic and therapeutic context of XPC

References

  1. Xeroderma pigmentosum group C protein interacts physically and functionally with thymine DNA glycosylase. Shimizu, Y., Iwai, S., Hanaoka, F., Sugasawa, K. EMBO J. (2003) [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. Combinations of polymorphisms in XPD, XPC and XPA in relation to risk of lung cancer. Vogel, U., Overvad, K., Wallin, H., Tjønneland, A., Nexø, B.A., Raaschou-Nielsen, O. Cancer Lett. (2005) [Pubmed]
  4. Antiproliferative activity of ecteinascidin 743 is dependent upon transcription-coupled nucleotide-excision repair. Takebayashi, Y., Pourquier, P., Zimonjic, D.B., Nakayama, K., Emmert, S., Ueda, T., Urasaki, Y., Kanzaki, A., Akiyama, S.I., Popescu, N., Kraemer, K.H., Pommier, Y. Nat. Med. (2001) [Pubmed]
  5. Deletion of XPC leads to lung tumors in mice and is associated with early events in human lung carcinogenesis. Hollander, M.C., Philburn, R.T., Patterson, A.D., Velasco-Miguel, S., Friedberg, E.C., Linnoila, R.I., Fornace, A.J. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  6. Associations between XPC expression, genotype, and the risk of head and neck cancer. Yang, M., Kang, M.J., Choi, Y., Kim, C.S., Lee, S.M., Park, C.W., Lee, H.S., Tae, K. Environ. Mol. Mutagen. (2005) [Pubmed]
  7. UV-induced ubiquitylation of XPC protein mediated by UV-DDB-ubiquitin ligase complex. Sugasawa, K., Okuda, Y., Saijo, M., Nishi, R., Matsuda, N., Chu, G., Mori, T., Iwai, S., Tanaka, K., Tanaka, K., Hanaoka, F. Cell (2005) [Pubmed]
  8. Characterization of molecular defects in xeroderma pigmentosum group C. Li, L., Bales, E.S., Peterson, C.A., Legerski, R.J. Nat. Genet. (1993) [Pubmed]
  9. High susceptibility to ultraviolet-induced carcinogenesis in mice lacking XPC. Sands, A.T., Abuin, A., Sanchez, A., Conti, C.J., Bradley, A. Nature (1995) [Pubmed]
  10. A novel regulation mechanism of DNA repair by damage-induced and RAD23-dependent stabilization of xeroderma pigmentosum group C protein. Ng, J.M., Vermeulen, W., van der Horst, G.T., Bergink, S., Sugasawa, K., Vrieling, H., Hoeijmakers, J.H. Genes Dev. (2003) [Pubmed]
  11. 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]
  12. Isolation of a cDNA encoding a UV-damaged DNA binding factor defective in xeroderma pigmentosum group E cells. Hwang, B.J., Liao, J.C., Chu, G. Mutat. Res. (1996) [Pubmed]
  13. Two essential splice lariat branchpoint sequences in one intron in a xeroderma pigmentosum DNA repair gene: mutations result in reduced XPC mRNA levels that correlate with cancer risk. Khan, S.G., Metin, A., Gozukara, E., Inui, H., Shahlavi, T., Muniz-Medina, V., Baker, C.C., Ueda, T., Aiken, J.R., Schneider, T.D., Kraemer, K.H. Hum. Mol. Genet. (2004) [Pubmed]
  14. Caffeine inhibits gene-specific repair of UV-induced DNA damage in hamster cells and in human xeroderma pigmentosum group C cells. Link, C.J., Evans, M.K., Cook, J.A., Muldoon, R., Stevnsner, T., Bohr, V.A. Carcinogenesis (1995) [Pubmed]
  15. The XPC poly-AT polymorphism in non-melanoma skin cancer. Nelson, H.H., Christensen, B., Karagas, M.R. Cancer Lett. (2005) [Pubmed]
  16. 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]
  17. New functions of XPC in the protection of human skin cells from oxidative damage. D'Errico, M., Parlanti, E., Teson, M., de Jesus, B.M., Degan, P., Calcagnile, A., Jaruga, P., Bjørås, M., Crescenzi, M., Pedrini, A.M., Egly, J.M., Zambruno, G., Stefanini, M., Dizdaroglu, M., Dogliotti, E. EMBO J. (2006) [Pubmed]
  18. Centrosome protein centrin 2/caltractin 1 is part of the xeroderma pigmentosum group C complex that initiates global genome nucleotide excision repair. Araki, M., Masutani, C., Takemura, M., Uchida, A., Sugasawa, K., Kondoh, J., Ohkuma, Y., Hanaoka, F. J. Biol. Chem. (2001) [Pubmed]
  19. 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]
  20. UV radiation-induced XPC translocation within chromatin is mediated by damaged-DNA binding protein, DDB2. Wang, Q.E., Zhu, Q., Wani, G., Chen, J., Wani, A.A. Carcinogenesis (2004) [Pubmed]
  21. 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]
  22. 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]
  23. In vivo recruitment of XPC to UV-induced cyclobutane pyrimidine dimers by the DDB2 gene product. Fitch, M.E., Nakajima, S., Yasui, A., Ford, J.M. J. Biol. Chem. (2003) [Pubmed]
  24. XPC and human homologs of RAD23: intracellular localization and relationship to other nucleotide excision repair complexes. van der Spek, P.J., Eker, A., Rademakers, S., Visser, C., Sugasawa, K., Masutani, C., Hanaoka, F., Bootsma, D., Hoeijmakers, J.H. Nucleic Acids Res. (1996) [Pubmed]
  25. Proficient global nucleotide excision repair in human keratinocytes but not in fibroblasts deficient in p53. Ferguson, B.E., Oh, D.H. Cancer Res. (2005) [Pubmed]
  26. Mutational inactivation of the xeroderma pigmentosum group C gene confers predisposition to 2-acetylaminofluorene-induced liver and lung cancer and to spontaneous testicular cancer in Trp53-/- mice. Cheo, D.L., Burns, D.K., Meira, L.B., Houle, J.F., Friedberg, E.C. Cancer Res. (1999) [Pubmed]
  27. Biochemical analysis of the damage recognition process in nucleotide excision repair. You, J.S., Wang, M., Lee, S.H. J. Biol. Chem. (2003) [Pubmed]
  28. Flexibility and plasticity of human centrin 2 binding to the xeroderma pigmentosum group C protein (XPC) from nuclear excision repair. Yang, A., Miron, S., Mouawad, L., Duchambon, P., Blouquit, Y., Craescu, C.T. Biochemistry (2006) [Pubmed]
  29. Structure of the XPC binding domain of hHR23A reveals hydrophobic patches for protein interaction. Kamionka, M., Feigon, J. Protein Sci. (2004) [Pubmed]
  30. Stable binding of human XPC complex to irradiated DNA confers strong discrimination for damaged sites. Batty, D., Rapic'-Otrin, V., Levine, A.S., Wood, R.D. J. Mol. Biol. (2000) [Pubmed]
  31. 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]
  32. Evidence for two independent pathways of biologically effective excision repair from its rate and extent in cells cultured from sun-sensitive humans. Tyrrell, R.M., Amaudruz, F. Cancer Res. (1987) [Pubmed]
  33. 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]
  34. Strong functional interactions of TFIIH with XPC and XPG in human DNA nucleotide excision repair, without a preassembled repairosome. Araújo, S.J., Nigg, E.A., Wood, R.D. Mol. Cell. Biol. (2001) [Pubmed]
  35. Single nucleotide polymorphisms in breast cancer. Försti, A., Angelini, S., Festa, F., Sanyal, S., Zhang, Z., Grzybowska, E., Pamula, J., Pekala, W., Zientek, H., Hemminki, K., Kumar, R. Oncol. Rep. (2004) [Pubmed]
  36. DNA repair factor XPC is modified by SUMO-1 and ubiquitin following UV irradiation. Wang, Q.E., Zhu, Q., Wani, G., El-Mahdy, M.A., Li, J., Wani, A.A. Nucleic Acids Res. (2005) [Pubmed]
  37. A multistep damage recognition mechanism for global genomic nucleotide excision repair. Sugasawa, K., Okamoto, T., Shimizu, Y., Masutani, C., Iwai, S., Hanaoka, F. Genes Dev. (2001) [Pubmed]
 
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