Mutations in the xeroderma pigmentosum group D DNA repair/transcription gene in patients with trichothiodystrophy

Broughton, Bernard C.; Steingrimsdottir, Herdis; Weber, Christine A.; Lehmann, Alan R.

doi:10.1038/ng0694-189

Cited by 124 publications

(66 citation statements)

References 31 publications

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“…Homologous genes designated XPB, XPD, p62, and p44, respectively, encode subunits of TFIIH(BTF2) in human cells (4,7,13,19,20). Mutations in the XPB and XPD genes are associated with several human hereditary diseases, including xeroderma pigmentosum, xeroderma pigmentosum with Cockayne's syndrome, and trichothiodystrophy (1,27).…”

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confidence: 99%

The Yeast TFB1 and SSL1 Genes, Which Encode Subunits of Transcription Factor IIH, Are Required for Nucleotide Excision Repair and RNA Polymerase II Transcription

Wang

Buratowski

Svejstrup

et al. 1995

Molecular and Cellular Biology

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The essential TFB1 and SSL1 genes of the yeast Saccharomyces cerevisiae encode two subunits of the RNA polymerase II transcription factor TFIIH (factor b). Here we show that extracts of temperature-sensitive mutants carrying mutations in both genes (tfb1-101 and ssl1-1) are defective in nucleotide excision repair (NER) and RNA polymerase II transcription but are proficient for base excision repair. RNA polymerase II-dependent transcription at the CYC1 promoter was normal at permissive temperatures but defective in extracts preincubated at a restrictive temperature. In contrast, defective NER was observed at temperatures that are permissive for growth. Additionally, both mutants manifested increased sensitivity to UV radiation at permissive temperatures. The extent of this sensitivity was not increased in a tfb1-101 strain and was only slightly increased in a ssl1-1 strain at temperatures that are semipermissive for growth. Purified factor TFIIH complemented defective NER in both tfb1-101 and ssl1-1 mutant extracts. These results define TFB1 and SSL1 as bona fide NER genes and indicate that, as is the case with the yeast Rad3 and Ssl2 (Rad25) proteins, Tfb1 and Ssl1 are required for both RNA polymerase II basal transcription and NER. Our results also suggest that the repair and transcription functions of Tfb1 and Ssl1 are separable.Transcription from mammalian or Saccharomyces cerevisiae promoters by RNA polymerase II requires multiple initiation factors, including TFIIB (factor e), TFIID (factor d), TFIIE (factor a), TFIIF (factor g), and TFIIH (factor b) (2, 6). The transcriptionally active form of factor b in a yeast reconstituted system in vitro is designated holo-TFIIH, comprising core TFIIH, Ssl2 protein, and the three-subunit kinase TFIIK (22). Core TFIIH with associated Ssl2 (core TFIIH-Ssl2) consists of six subunits of ϳ105, 85, 70, 50, 55, and 38 kDa (6,22). The first four subunits have been identified as the products of the SSL2 (RAD25), RAD3, TFB1, and SSL1 genes, respectively (6,10,22). Homologous genes designated XPB, XPD, p62, and p44, respectively, encode subunits of TFIIH(BTF2) in human cells (4,7,13,19,20). Mutations in the XPB and XPD genes are associated with several human hereditary diseases, including xeroderma pigmentosum, xeroderma pigmentosum with Cockayne's syndrome, and trichothiodystrophy (1, 27).Core TFIIH-Ssl2 is required for both transcription by RNA polymerase II and nucleotide excision repair (NER) in S. cerevisiae and humans (4,23,25,28). Consistent with their requirement for transcription, SSL2, RAD3, TFB1, and SSL1 are essential yeast genes (10-12, 17, 18, 34). The same presumably holds true for the homologous human genes, though the essentiality of gene function is difficult to demonstrate directly for mammalian cells.Recent studies have shown that cell extracts of viable yeast rad3 and ssl2 mutants are defective in NER (28). These defects can be corrected by complementation of the extracts with purified core TFIIH or core TFIIH-Ssl2 complexes, respectively, but not by complem...

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confidence: 99%

The Yeast TFB1 and SSL1 Genes, Which Encode Subunits of Transcription Factor IIH, Are Required for Nucleotide Excision Repair and RNA Polymerase II Transcription

Wang

Buratowski

Svejstrup

et al. 1995

Molecular and Cellular Biology

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“…It has been proposed that subtle alterations in transcription, caused by mutations in TFIIH subunits, can result in deficiencies in certain proteins whose expression is critically dependent on the level of transcription (35,37). Furthermore it has been suggested that the features of XP largely result from defective DNA repair, whereas many of the features of TTD may be a consequence of transcriptional alterations (14,35,37). The finding that the causative mutations in the XPD gene are located at different sites within the gene in XP-D and TTD patients (refs.…”

Section: Discussionmentioning

confidence: 99%

Photocarcinogenesis and inhibition of intercellular adhesion molecule 1 expression in cells of DNA-repair-defective individuals

Ahrens

Grewe

Berneburg

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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Cells from patients with xeroderma pigmentosum complementation group D (XP-D) and most patients with trichothiodystrophy (TTD) are deficient in excision repair of ultraviolet (UV) radiation-induced DNA damage. Although in both syndromes this defect is based on mutations in the same gene, XPD, only XP-D, not TTD, individuals have an increased risk of skin cancer. Since the reduction in DNA repair capacity is similar in XP-D and TTD patients, it cannot account for the difference in skin cancer risk. The features of XP-D and TTD might therefore be attributable to differences in the immune response following UV-irradiation, a factor which is presumed to be important for photocarcinogenesis. Sunlight-induced skin cancer represents the most prevalent malignancy in the Caucasian population, and its incidence is increasing (1). The pathogenesis of photocarcinogenesis is complex and only partially understood. Sunlight is a complete carcinogen, and it is generally accepted that ultraviolet B (UVB; 290-320 nm) radiation-induced DNA mutations constitute the initiation event for the generation of malignant skin cells (2). Studies in animals, however, provide evidence for a second mechanism for the development of clinically apparent skin cancer following UVB radiation exposure. In these studies, UVB radiation at subcarcinogenic doses was found to inhibit the surveillance function of the skin immune system directed against UVB radiation-induced skin tumors (3, 4). The importance of this second mechanism for photocarcinogenesis was demonstrated in tumor transplantation studies in mice, which cannot be carried out in humans. The evidence for a role of UVB radiation-induced immunosuppression in human skin cancer is therefore inevitably circumstantial and includes the observation that immunosuppressed humans who have received renal transplants have an increased frequency of sunlight-induced skin cancers (5-8).Here we take advantage of two human syndromes associated with defects in excision repair of UV-induced DNA lesions, namely xeroderma pigmentosum complementation group D (XP-D) and trichothiodystrophy (TTD) (9-11). Cells derived from XP-D and the majority of TTD patients have a defect in nucleotide excision repair (12, 13), which results from mutations in the same gene (XPD) (refs. 14-16 and unpublished results of B. C. Broughton and A.R.L.). Despite this similarity and a similar frequency of UV-induced mutations (17), only XP-D patients have an increased risk of developing skin cancer (10, 11). Since the increased risk of skin cancer in XP-D, as compared with TTD patients, cannot be explained simply by differences in DNA repair capacity, we hypothesized that XP-D and TTD cells might differ in some aspect of the immune response after UVB radiation.To test this hypothesis, the capacity of UVB radiation to suppress transcriptional expression of the intercellular adhesion molecule 1 (ICAM-1) was assessed in comparative studies employing XP-D and TTD cells. ICAM-1 serves as a ligand for leukocyte function-associated antige...

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“…The first was the cloning of the ERCC2 gene by Christine Webber and Larry Thompson and demonstration that this was the XPD gene [61], the second was the seminal discovery by the group of Jean-Marc Egly in collaboration with the Rotterdam group that XPB and XPD were components of the transcription factor TFIIH, which had two functions, in NER and transcription [62]. Following on from these exciting findings we were able to identify the first mutations in the XPD gene, in TTD patients [63], and subsequently in many others and, importantly, we were able to show that each mutation site is disease-specific. R683W, found in the majority of XP patients in the XP-D group, has never been found in a TTD patient, whereas, R112H and R722W, fairly common in TTD, are never found in XP patients [64].…”

Section: Xp Variants Cockayne Syndrome and Other Repair-deficient DImentioning

confidence: 95%

DNA repair, DNA replication and human disorders: A personal journey

Lehmann

2012

DNA Repair

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Mutations in the xeroderma pigmentosum group D DNA repair/transcription gene in patients with trichothiodystrophy

Cited by 124 publications

References 31 publications

The Yeast TFB1 and SSL1 Genes, Which Encode Subunits of Transcription Factor IIH, Are Required for Nucleotide Excision Repair and RNA Polymerase II Transcription

The Yeast TFB1 and SSL1 Genes, Which Encode Subunits of Transcription Factor IIH, Are Required for Nucleotide Excision Repair and RNA Polymerase II Transcription

Photocarcinogenesis and inhibition of intercellular adhesion molecule 1 expression in cells of DNA-repair-defective individuals

DNA repair, DNA replication and human disorders: A personal journey

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