Abstract
DNA repair defects in the xeroderma pigmentosum (XP) group D complementation group can be associated with the clinical features of two quite different disorders; XP, a sun–sensitive and cancer–prone disorder, or trichothiodystrophy (TTD) which is characterized by sulphur–deficient brittle hair and a variety of other associated abnormalities, but no skin cancer. The XPD gene product, a DNA helicase, is required for nucleotide excision repair and recent evidence has demonstrated a role in transcription. We have now identified causative mutations in XPD in four TTD patients. The patients are all compound heterozygotes and the locations of the mutations enable us to suggest relationships between different domains in the gene and its roles in excision repair and transcription.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Hoeijmakers, J.H.J. Nucleotide excision repair II: from yeast to mammals. Trends Genet. 9, 211–217 (1993).
Itin, P.H. & Pittelkow, M.R. Trichothiodystrophy: review of sulfur-deficient brittle hair syndromes and association with the ectodermal dysplasias. J. Am. Acad. Dermatol., 20, 705–717 (1990).
Stefanini, M. et al. Xeroderma pigmentosum (complementation group D) mutation is present in patients affected by trichothiodystrophy with photosensitivity. Hum. Genet. 74, 107–112 (1986).
Stefanini, M. et al. DNA repair investigations in nine Italian patients affected by trichothiodystrophy. Mutation Res. 273, 119–125 (1992).
Stefanini, M. et al. Genetic heterogeneity of the excision repair defect associated with trichothiodystrophy. Carcinogenesis 14, 1101–1105 (1993).
Stefanini, M. et al. A new nucleotide excision repair gene associated with the genetic disorder trichothiodystrophy. Am. J. hum. Genet. 53, 817–821 (1993).
Lehmann, A.R. and Norris, P.G. DNA repair and cancer: speculations based on studies with xeroderma pigmentosum, Cockayne's syndrome and trichothiodystrophy. Carcinogenesis, 10, 1353–1356 (1989).
Weber, C.A., Salazar, E.P., Stewart, S.A. & Thompson, L.H. Molecular cloning and biological characterization of a human gene, ERCC2, that corrects the nucleotide excision repair defect in CHO UV5 cells. Molec. cell Biol. 8, 1137–1146 (1988).
Lehmann, A.R. et al. Workshop on DNA repair. Mutation Res. 273, 1–28 (1992).
Flejter, W.L., McDaniel, L.D., Johns, D., Friedberg, E.C. & Schultz, R.A. Correction of xeroderma pigmentosum complementation group D mutant cell phenotypes by chromosome and gene transfer: Involvement of the human ERCC2 DNA repair gene. Proc. natn. Acad. Sci. U.S.A. 89, 261–265 (1992).
Weber, C.A., Salazar, E.P., Stewart, S.A. & Thompson, L.H. ERCC-2: cDNA cloning and molecular characterization of a human nucleotide excision repair gene with high homology to yeast RAD3. EMBO J. 9, 1437–1448 (1990).
Murray, J.M. et al. Cloning and characterisation of the S. pombe rad 15 gene, a homologue to the S. cerevisiae RAD3 and human ERCC2 genes. Nucl. Acids Res. 20, 2673–2678 (1992).
Reynolds, P.R., Biggar, S., Prakash, L. & Prakash, S. The Schizosaccharomyces pombe rhp3+ gene required for DNA repair and cell viability is functionally interchangeable with the RAD3 gene of Saccharomyces cerevisiae. Nucl. Acids Res. 20, 2327–2334 (1992).
Sung, P., Prakash, L., Matson, S.W. & Prakash, S. RAD3 protein of Saccharomyces cerevisiae is a DNA helicase. Proc. natn. Acad. Sci. U.S.A. 84, 8951–8955 (1987).
Sung, P. et al. Human xeroderma pigmentosum group D gene encodes a DNA helicase. Nature 365, 852–855 (1993).
Schaeffer, L. et al. DNA repair helicase: a component of BTF2 (TFIIH) basic transcription factor. Science 260, 58–63 (1993).
Drapkin, R. et al. Dual role of TFIIH in DNA excision repair and in transcription by RNA polymerase II. Nature 368, 769–772 (1994).
Feaver, W.J. et al. Dual roles of a multiprotein complex from S. cerevisiae in transcription and DNA repair. Cell 75, 1379–1387 (1993).
Lehmann, A.R. et al. Trichothiodystrophy, a human DNA repair disorder with heterogeneity in the cellular response to ultraviolet light. Cancer Res. 48, 6090–6096 (1988).
Broughton, B.C. et al. Relationship between pyrimidine dimers, 6-4 photoproducts, repair synthesis and cell survival: Studies using cells from patients with triohothiodystrophy. Mutation Res. 235, 33–40 (1990).
Tolmie, J.L. et al. Syndromes associated with trichothiodystrophy. Clin. Dysmorphol. 3, 1–14 (1994).
King, M.D., Gummer, C.L. & Stephenson, J.B.P. Trichothiodystrophy-neurotrichocutaneous syndrome of Pollitt: a report of two unrelated cases. J. med. Genet. 21, 286–289 (1984).
Cooper, D.N. & Krawzcak, M. The mutational spectrum of single base-pair substitutions causing human genetic disease in patterns and predictions. Hum. Genet. 85, 55–74 (1990).
Streisinger, G. et al. Frameshift mutations and the genetic code. Cold Spring Harbour Symp. Quant. Biol. 31, 77–84 (1966).
Bailly, V., Sung, P., Prakash, L. & Prakash, S. DNA.RNA helicase activity of RAD3 protein of Saccharomyces cerevisiae. Proc. natn. Acad. Sci. U.S.A. 88, 9712–9716 (1991).
Naegeli, H., Bardwell, L., Harosh, I. & Friedberg, E.C. Substrate specificity of the Rad3 ATPase/DNA helicase of Saccharomyces cerevisiae and binding of Rad3 protein to nucleic acids. J. biol. Chem. 267, 7839–7844 (1992).
Friedberg, E.C. Deoxyribonucleic acid repair in the yeast Saccharomyces cerevisiae. Microbiol. Rev. 52, 70–102 (1988).
Naumovski, L. & Friedberg, E.C. Analysis of the essential and excision repair functions of the RAD3 gene of Saccharomyces cerevisiae by mutagenesis. Molec. cell. Biol. 6, 1218–1227 (1986).
Song, J.M., Montelone, B.A., Siede, W. & Friedberg, E.C. Effects of multiple yeast rad3 mutant alleles on UV sensitivity, mutability, and mitotic recombination. J. Bacteriology 172, 6620–6630 (1990).
Gorbalenya, A.E., Koonin, E.V., Donchenko, A.P. & Blinov, V.M. Two related super families of putative helicases involved in replication, recombination, repair and expression of DNA and RNA genomes. Nucl. Acids Res. 17, 4713–4730 (1989).
Harosh, I. & Deschavanne, P. The RAD3 gene is a member of the DEAH family RNA helicase-like protein. Nucl. Acids Res. 19, 6331 (1991).
Sung, P., Higgins, D., Prakash, L. & Prakash, S. Mutation of lysine-48 to arginine in the yeast RAD3 protein abolishes its ATPase and DNA helicase activities but not the ability to bind ATP. EMBO J., 7, 3263–3269 (1988).
Kovalic, D., Kwak, J.-H. & Weisblum, B. General method for direct cloning of DNA fragments generated by the polymerase chain reaction. Nucl. Acids Res. 19, 4560 (1991).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Broughton, B., Steingrimsdottir, H., Weber, C. et al. Mutations in the xeroderma pigmentosum group D DNA repair/transcription gene in patients with trichothiodystrophy. Nat Genet 7, 189–194 (1994). https://doi.org/10.1038/ng0694-189
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ng0694-189
This article is cited by
-
Genome instability syndromes caused by impaired DNA repair and aberrant DNA damage responses
Cell Biology and Toxicology (2018)
-
Mechanisms of interstrand DNA crosslink repair and human disorders
Genes and Environment (2016)
-
Uncommon nucleotide excision repair phenotypes revealed by targeted high-throughput sequencing
Orphanet Journal of Rare Diseases (2016)
-
A Japanese trichothiodystrophy patient with XPD mutations
Journal of Human Genetics (2011)
-
XPD Common Variants and their Association with Melanoma and Breast Cancer Risk
Breast Cancer Research and Treatment (2006)