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Gene Review

Xpa  -  xeroderma pigmentosum, complementation...

Mus musculus

Synonyms: AI573865, DNA repair protein complementing XP-A cells homolog, Xeroderma pigmentosum group A-complementing protein homolog, Xpac
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Disease relevance of Xpa

  • To examine whether these p53 patches can be used as tumour risk indicators, we made an extensive comparison of the induction kinetics of these patches and carcinomas in genetically modified mice with various defects in nucleotide excision repair (NER), i.e. xeroderma pigmentosum A (Xpa), Xpc and Cockayne syndrome B (Csb) and wild-type mice [1].
  • Subsequently Xpa and Xpc knockouts have proved to be good models for the human NER deficiency disease, xeroderma pigmentosum, leading to speculation that the recombination, rather than the NER deficit is the key to the Ercc1 knockout phenotype [2].
  • These features were not seen in nucleotide excision repair-deficient Xpa-/- mice, but are characteristic of Fanconi anemia, a human cancer syndrome caused by defects in interstrand crosslink repair [3].
  • On UVB treatment (250 J/m(2)), Xpa(-/-) and Csb(-/-) mice revealed an extensive apoptotic response in the skin, a blockage of cell cycle progression of epidermal cells, and strong hyperplasia [4].
  • Despite raising >1,600 nevi, only six melanomas arose in our experiments with Ink4a/Arf knockout mice (five of which in Xpa(+/+) mice at high UV dosages) [5].

High impact information on Xpa

  • We investigated the impact of deficiencies in NER subpathways on apoptosis, hyperplasia, and cell cycle progression in the epidermis of UVB-exposed CS group B (Csb(-/-)) mice (no TCR), XP group C (Xpc(-/-)) mice (no GGR), and XP group A (Xpa(-/-)) mice (no TCR and no GGR) [4].
  • Therefore, hypermutation was studied in mice deficient for either the DNA nucleotide excision repair gene Xpa or the mismatch repair gene Pms2 [6].
  • The Xpa(-/-) mice proved exquisitely sensitive to UV-driven nevus induction, indicating the involvement of pyrimidine dimer DNA lesions, but Xpa(+/+) mice developed many more nevi (>40 per mouse) at high UV dosages not tolerated by Xpa(-/-) mice [5].
  • p53 heterozygosity results in an increased 2-acetylaminofluorene-induced urinary bladder but not liver tumor response in DNA repair-deficient Xpa mice [7].
  • Short-term assays revealed a decreased apoptotic response in Xpa/p53(+/-) mice, pointing in vivo toward a link between NER and p53-mediated apoptosis [7].

Biological context of Xpa

  • Xpa mice completely lack the nucleotide excision repair pathway, and as such they are sensitive to some classes of genotoxic compounds [8].
  • It is concluded that while increased genomic instability could play a causal role in the mildly accelerated aging phenotype in the Xpa-null mice or in the severe progeroid symptoms of the Ercc1-mutant mice, shortened lifespan in mice with defects in transcription-related repair do not depend upon increased mutation accumulation [9].
  • Repair-defective Xpa-/- mice were 7-10-fold more sensitive to sunburn cell induction than wild-type mice, indicating that 86-90% of the ultraviolet B signal for keratinocyte apoptosis involved repairable photoproducts in DNA; the remainder involves unrepaired DNA lesions or nongenomic targets [10].
  • Homozygous inactivation of Xpa, Csb, or Xpc nucleotide excision repair genes directed the accumulation of DNA photoproducts to specific genome regions [10].
  • Interestingly, however, mice completely deficient in both NER and p53 (Xpa/p53(-/-) mice) showed a dramatic increase of hepatocellular proliferation accompanied by lacZ reporter gene mutations [7].

Anatomical context of Xpa


Associations of Xpa with chemical compounds


Other interactions of Xpa

  • Phenacetin exposure induced a significant increase of lacZ mutations in the kidney of both Xpa and Xpa/p53 mice [8].
  • Here we show that this mutation is not a hot spot in Xpa or Csa mutant mice [18].
  • Hprt mutant frequencies in Xpa-/- and Csb-/- mice that both have a defect in this NER subpathway, remained low during ageing [19].
  • In this study, we investigated the impact of loss of XPA function on PhIP-induced intestinal tumorigenesis in F1 offspring of Min/+ (Apc(+/-)) mice crossed with Xpa gene-deficient mice [20].
  • Severe growth retardation and short life span of double-mutant mice lacking Xpa and exon 15 of Xpg [21].

Analytical, diagnostic and therapeutic context of Xpa

  • Surprisingly, while all intraperitoneally-treated Xpc(-/-) mice survived a dose of 40 mg/kg DMBA, a substantial fraction of the treated Xpa(-/-) and Csb(-/-) mice died a few days after treatment with a 20-fold lower dose [11].
  • The DFMO treatment reduced the tumor load but did not offer the Xpa knockout mice full protection against UV carcinogenesis [16].
  • All compounds identified thus far are true (human) carcinogens, and, therefore, the authors believe that the Xpa/p53+/- mouse model is an excellent candidate for a future replacement of the chronic mouse bioassay, at least for certain classes of chemicals [22].


  1. Relationship between UV-induced mutant p53 patches and skin tumours, analysed by mutation spectra and by induction kinetics in various DNA-repair-deficient mice. Rebel, H., Kram, N., Westerman, A., Banus, S., van Kranen, H.J., de Gruijl, F.R. Carcinogenesis (2005) [Pubmed]
  2. DNA repair gene Ercc1 is essential for normal spermatogenesis and oogenesis and for functional integrity of germ cell DNA in the mouse. Hsia, K.T., Millar, M.R., King, S., Selfridge, J., Redhead, N.J., Melton, D.W., Saunders, P.T. Development (2003) [Pubmed]
  3. Reduced hematopoietic reserves in DNA interstrand crosslink repair-deficient Ercc1-/- mice. Prasher, J.M., Lalai, A.S., Heijmans-Antonissen, C., Ploemacher, R.E., Hoeijmakers, J.H., Touw, I.P., Niedernhofer, L.J. EMBO J. (2005) [Pubmed]
  4. Differential role of transcription-coupled repair in UVB-induced G2 arrest and apoptosis in mouse epidermis. van Oosten, M., Rebel, H., Friedberg, E.C., van Steeg, H., van der Horst, G.T., van Kranen, H.J., Westerman, A., van Zeeland, A.A., Mullenders, L.H., de Gruijl, F.R. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  5. Induction of nevi and skin tumors in Ink4a/Arf Xpa knockout mice by neonatal, intermittent, or chronic UVB exposures. van Schanke, A., van Venrooij, G.M., Jongsma, M.J., Banus, H.A., Mullenders, L.H., van Kranen, H.J., de Gruijl, F.R. Cancer Res. (2006) [Pubmed]
  6. Altered spectra of hypermutation in antibodies from mice deficient for the DNA mismatch repair protein PMS2. Winter, D.B., Phung, Q.H., Umar, A., Baker, S.M., Tarone, R.E., Tanaka, K., Liskay, R.M., Kunkel, T.A., Bohr, V.A., Gearhart, P.J. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  7. p53 heterozygosity results in an increased 2-acetylaminofluorene-induced urinary bladder but not liver tumor response in DNA repair-deficient Xpa mice. Hoogervorst, E.M., van Oostrom, C.T., Beems, R.B., van Benthem, J., Gielis, S., Vermeulen, J.P., Wester, P.W., Vos, J.G., de Vries, A., van Steeg, H. Cancer Res. (2004) [Pubmed]
  8. Phenacetin acts as a weak genotoxic compound preferentially in the kidney of DNA repair deficient Xpa mice. Luijten, M., Speksnijder, E.N., van Alphen, N., Westerman, A., Heisterkamp, S.H., van Benthem, J., van Kreijl, C.F., Beems, R.B., van Steeg, H. Mutat. Res. (2006) [Pubmed]
  9. Increased genomic instability is not a prerequisite for shortened lifespan in DNA repair deficient mice. Dollé, M.E., Busuttil, R.A., Garcia, A.M., Wijnhoven, S., van Drunen, E., Niedernhofer, L.J., van der Horst, G., Hoeijmakers, J.H., van Steeg, H., Vijg, J. Mutat. Res. (2006) [Pubmed]
  10. The DNA damage signal for Mdm2 regulation, Trp53 induction, and sunburn cell formation in vivo originates from actively transcribed genes. Brash, D.E., Wikonkal, N.M., Remenyik, E., van der Horst, G.T., Friedberg, E.C., Cheo, D.L., van Steeg, H., Westerman, A., van Kranen, H.J. J. Invest. Dermatol. (2001) [Pubmed]
  11. DMBA-induced toxic and mutagenic responses vary dramatically between NER-deficient Xpa, Xpc and Csb mice. Wijnhoven, S.W., Kool, H.J., Mullenders, L.H., Slater, R., van Zeeland, A.A., Vrieling, H. Carcinogenesis (2001) [Pubmed]
  12. Mismatch repair protein Msh2 contributes to UVB-induced cell cycle arrest in epidermal and cultured mouse keratinocytes. van Oosten, M., Stout, G.J., Backendorf, C., Rebel, H., de Wind, N., Darroudi, F., van Kranen, H.J., de Gruijl, F.R., Mullenders, L.H. DNA Repair (Amst.) (2005) [Pubmed]
  13. Diethylstilbestrol (DES): carcinogenic potential in Xpa-/-, Xpa-/- / p53+/-, and wild-type mice during 9 months' dietary exposure. McAnulty, P.A., Skydsgaard, M. Toxicologic pathology. (2005) [Pubmed]
  14. Role of nucleotide- and base-excision repair in genotoxin-induced neuronal cell death. Kisby, G.E., Lesselroth, H., Olivas, A., Samson, L., Gold, B., Tanaka, K., Turker, M.S. DNA Repair (Amst.) (2004) [Pubmed]
  15. Single UVB overexposure stimulates melanocyte proliferation in murine skin, in contrast to fractionated or UVA-1 exposure. van Schanke, A., Jongsma, M.J., Bisschop, R., van Venrooij, G.M., Rebel, H., de Gruijl, F.R. J. Invest. Dermatol. (2005) [Pubmed]
  16. Suppression of UV carcinogenesis by difluoromethylornithine in nucleotide excision repair-deficient Xpa knockout mice. Rebel, H., van Steeg, H., Beems, R.B., Schouten, R., de Gruijl, F.R., Terleth, C. Cancer Res. (2002) [Pubmed]
  17. Assessment of carcinogenicity of di(2-ethylhexyl)phthalate in a short-term assay using Xpa-/- and Xpa-/-/p53+/- mice. Mortensen, A., Bertram, M., Aarup, V., Sørensen, I.K. Toxicologic pathology. (2002) [Pubmed]
  18. Mutations in the Trp53 gene of UV-irradiated Xpc mutant mice suggest a novel Xpc-dependent DNA repair process. Nahari, D., McDaniel, L.D., Task, L.B., Daniel, R.L., Velasco-Miguel, S., Friedberg, E.C. DNA Repair (Amst.) (2004) [Pubmed]
  19. Age-dependent spontaneous mutagenesis in Xpc mice defective in nucleotide excision repair. Wijnhoven, S.W., Kool, H.J., Mullenders, L.H., van Zeeland, A.A., Friedberg, E.C., van der Horst, G.T., van Steeg, H., Vrieling, H. Oncogene (2000) [Pubmed]
  20. Role of nucleotide excision repair deficiency in intestinal tumorigenesis in multiple intestinal neoplasia (Min) mice. Steffensen, I.L., Schut, H.A., Nesland, J.M., Tanaka, K., Alexander, J. Mutat. Res. (2006) [Pubmed]
  21. Severe growth retardation and short life span of double-mutant mice lacking Xpa and exon 15 of Xpg. Shiomi, N., Mori, M., Kito, S., Harada, Y.N., Tanaka, K., Shiomi, T. DNA Repair (Amst.) (2005) [Pubmed]
  22. DNA repair-deficient Xpa and Xpa/p53+/- knock-out mice: nature of the models. van Steeg, H., de Vries, A., van Oostrom CTh, n.u.l.l., van Benthem, J., Beems, R.B., van Kreijl, C.F. Toxicologic pathology. (2001) [Pubmed]
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