Codominance associated with overexpression of certain XPD mutations

S. Kadkhodayan, F. Coin, E. P. Salazar, J. W. George, J. M. Egly, L. H. Thompson

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Mutations in the XPD gene are associated with three complex clinical phenotypes, namely xeroderma pigmentosum (XP), XP in combination with Cockayne syndrome (XP-CS), and trichothiodystrophy (TTD). XP is caused by a deficiency in nucleotide excision repair (NER) that results in a high risk of skin cancer. TTD is characterized by severe developmental and neurological defects, with hallmark features of brittle hair and scaly skin, and sometimes has defective NER. We used CHO cells as a system to study how specific mutations alter the dominant/recessive behavior of XPD protein. Previously we identified the T46I and R75W mutations in two highly UV-sensitive hamster cell lines that were reported to have paradoxically high levels of unscheduled DNA synthesis. Here we report that these mutants have greatly reduced XPD helicase activity and fully defective NER in a cell-extract excision assay. We conclude that the unscheduled DNA synthesis seen in these mutants is caused by abortive "repair" that does not contribute to cell survival. These mutations, as well as the K48R canonical helicase-domain mutation, each produced codominant negative phenotypes when overexpressed in wild-type CHO cells. The common XP-specific R683W mutation also behaved in a codominant manner when overexpressed, which is consistent with the idea that this mutation may affect primarily the enzymatic activity of the protein rather than impairing protein interactions, which may underlie TTD. A C-terminal mutation uniquely found in TTD (R722W) was overexpressed but not to levels sufficiently high to rigorously test for a codominant phenotype. Overexpression of mutant XPD alleles may provide a simple means of producing NER deficiency in other cell lines.

Original languageEnglish (US)
Pages (from-to)153-168
Number of pages16
JournalMutation Research - DNA Repair
Issue number2
StatePublished - Mar 7 2001
Externally publishedYes


  • Nucleotide-excision repair
  • Trichothiodystrophy
  • Xeroderma pigmentosum
  • XPD mutations

ASJC Scopus subject areas

  • Toxicology
  • Genetics
  • Molecular Biology


Dive into the research topics of 'Codominance associated with overexpression of certain XPD mutations'. Together they form a unique fingerprint.

Cite this