Polymorphisms in the human xeroderma pigmentosum group A gene and their impact on cell survival and nucleotide excision repair

Isabel Mellon, Thomas Hock, Rollie Reid, Paul C. Porter, J. Christopher States

Research output: Contribution to journalArticlepeer-review

34 Scopus citations


Polymorphisms in DNA repair genes may contribute to defects in DNA repair and increased susceptibility to cancer. The xeroderma pigmentosum group A (XPA) gene is required for nucleotide excision repair (NER) and mutations in XPA highly predispose humans to skin cancer. We examined DNA samples from 189 individuals for polymorphisms in the XPA gene. First, SSCP analysis was used to examine each of the six exons and their intron boundaries. One frequent single nucleotide polymorphism (SNP) in the untranslated region of exon 1 and two rare SNPs which produce the changes Arg228Gln and Val234Leu in the coding region of exon 6 were identified. Quite surprisingly, no sequence variants were found within the coding regions or the adjacent intron boundaries of exons 1-5. Ecdysone-inducible expression vectors containing wild type XPA cDNA or cDNAs representing the two polymorphisms that we identified in exon 6 were created and independently introduced into the XPA deficient cell line XP12RO-SV. Transcription-coupled repair (TCR), global genome repair (GGR) and cell survival following UV irradiation were studied in each cell line in the absence or presence of the ecdysone hormone analog, ponasterone A. No substantial difference in repair or cell survival was found in cells complemented with wild type or polymorphic alleles of XPA. A 10-fold increase in the expression of XPA by addition of ponasterone A resulted in faster removal of 6-4 photoproducts from the total genomes of cells complemented with wild type or polymorphic alleles of XPA but had no significant impact on TCR or global genome repair of cyclobutane pyrimidine dimers (CPDs). Since our SSCP analysis failed to detect significant numbers of polymorphisms we directly sequenced exons 4-6 in a subset of our samples. One additional rare SNP, which produces the change Leu252Val was found in exon 6 and four rare SNPs and one rare single nucleotide deletion were found in intron 4. Hence, the XPA gene appears to be a cold spot for genetic variation and rare polymorphisms in the coding region of the gene do not reduce NER or cell survival after UV irradiation.

Original languageEnglish
Pages (from-to)531-546
Number of pages16
JournalDNA Repair
Issue number7
StatePublished - Jul 17 2002

Bibliographical note

Funding Information:
We thank Dr. Maura Pieretti for helpful discussions during the initial stages of this project and Dr. Mitchell Turker for helpful suggestions and critical reading of the manuscript. This work was supported by Grant nos. RO1GM45535 from the National Institute of General Medicine and DAMD17-98-1-8201 from the Department of Defense to I.M., pilot project funding from the Markey Cancer Center to I.M. and The Kentucky Research Challenge Trust Fund and pilot project funding from NIH Grant no. RR11803 to J.C.S.


  • DNA repair
  • Genetic polymorphisms
  • Global genome repair
  • Transcription-coupled repair
  • XPA gene
  • Xeroderma pigmentosum

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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