Genes controlling nucleotide excision repair in eukaryotic cells

Weeda, Geert; Hoeijmakers, Jan H.J.; Bootsma, D.

doi:10.1002/bies.950150405

Cited by 48 publications

(20 citation statements)

References 53 publications

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“…One intriguing speculation is that RAD3 and its mammalian homolog XPD (60,67) are both involved in the maintenance of genome integrity. This would give further support to previous observations (56) that, like several other DNA repair pathways (12,68), recombination is conserved in S. cerevisiae and humans.…”

Section: Discussionsupporting

confidence: 90%

The Essential Helicase Gene RAD3 Suppresses Short-Sequence Recombination in Saccharomyces cerevisiae

Bailis

Maines

Negritto

1995

Molecular and Cellular Biology

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We have isolated an allele of the essential DNA repair and transcription gene RAD3 that relaxes the restriction against recombination between short DNA sequences in Saccharomyces cerevisiae. Double-strand break repair and gene replacement events requiring recombination between short identical or mismatched sequences were stimulated in the rad3-G595R mutant cells. We also observed an increase in the physical stability of double-strand breaks in the rad3-G595R mutant cells. These results suggest that the RAD3 gene suppresses recombination involving short homologous sequences by promoting the degradation of the ends of broken DNA molecules.All organisms must repair the damage to their DNA that results from environmental stress and normal metabolism. Genetic recombination is one of several pathways that have evolved to repair this damage (13). This mode of repair can lead to deleterious consequences, however, because recombination between dispersed duplicate (ectopic) sequences can result in genome rearrangements or gene inactivation or both (42). These events are also implicated in human disease (20,24). Both DNA sequence length (2,26,51,53,58) and identity (6,18,36,43,45,47) are important determinants of the rate of recombination between repeated DNA sequences. What remains largely unclear is how short sequence length and mismatching hinder recombination. We took a genetic approach to studying the control of ectopic recombination in Saccharomyces cerevisiae. In a search for mutants that stimulate this recombination, we isolated an allele of the RAD3 gene (rad3-G595R) that increased the rate of recombination between sequences that share short lengths of perfect or imperfect homology.The RAD3 gene encodes a helicase (61) that is an essential component of the transcription and DNA repair complex TFIIH (factor B [10,66]) and is highly homologous to the human nucleotide excision repair gene XPD (60, 67). Many rad3 mutants have been isolated (13). These mutants exhibit a wide array of overlapping phenotypes including altered transcription (16), DNA repair (40,48,72), and recombination (37). One set of mutants, originally designated rem, were identified on the basis of their mutator and hyperrecombination phenotypes (14). The rem genes were subsequently found to be alleles of RAD3 and are thought to lead to the creation of recombinogenic double-strand breaks (37). Another mutant allele, rad3-2, is not hyperrecombinant but does decrease gene conversion tract length during intrachromosomal recombination (1). These diverse recombination phenotypes may be due to defects in the transcription of important recombination genes or to direct effects of mutant Rad3 proteins on recombination.White and Haber (71) analyzed the repair of double-strand breaks in DNA by homologous recombination between unlinked, duplicate sequences at the molecular level and showed that double-strand breaks are subject to extensive 5Ј-end degradation in wild-type cells. This processing is thought to be crucial for producing a single-stranded 3Ј end (3, 7...

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Section: Discussionsupporting

confidence: 90%

The Essential Helicase Gene RAD3 Suppresses Short-Sequence Recombination in Saccharomyces cerevisiae

Bailis

Maines

Negritto

1995

Molecular and Cellular Biology

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“…However, our finding that mutations in p53 alter global but not transcription-coupled DNA repair suggests potential targets. For example, a number of genes have now been identified that encode different proteins involved in human NER, which when mutated are responsible for the different complementation groups of the human NERdeficiency syndromes xeroderma pigmentosum (XP) and Cockayne syndrome (CS) (22). The resultant repair deficiency in cells from each complementation group depends upon the function of the altered gene product, and certain groups exhibit selective deficiencies in either overall or transcriptioncoupled repair.…”

Section: Methodsmentioning

confidence: 99%

Li-Fraumeni syndrome fibroblasts homozygous for p53 mutations are deficient in global DNA repair but exhibit normal transcription-coupled repair and enhanced UV resistance.

Ford

Hanawalt

1995

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

307

154

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We investigated whether mutations in the p53 tumor suppressor gene alter UV sensitivity and/or repair of UV-induced DNA damage in primary human skin fibroblasts from patients with Li-Fraumeni syndrome, heterozygous for mutations in one allele of the p53 gene (p53 wt/mut) and sublines expressing only mutant p53 (p53 mut). The p53 mut cells were more resistant than the p53 wt/mut cells to UV cytotoxicity and exhibited less UV-induced apoptosis. DNA repair analysis revealed reduced removal of cyclobutane pyrimidine dimers from overall genomic DNA in vivo in p53 mut cells compared with p53 wt/mut or normal cells. However, p53 mut cells retained the ability to preferentially repair damage in the transcribed strands of expressed genes (transcription-coupled repair). These results suggest that loss of p53 function may lead to greater genomic instability by reducing the efficiency of DNA repair but that cellular resistance to DNA-damaging agents may be enhanced through elimination of apoptosis.The molecular mechanisms that regulate responses of normal and neoplastic human cells to DNA damage are important both to the process of carcinogenesis and to the action of cancer therapeutic agents. The protein product of the p53 tumor suppressor gene appears to be critical in mediating certain cellular responses to DNA damage in mammalian cells and is involved in both cell cycle regulation and apoptotic cell death (1-3). Wild-type (wt) p53 protein is activated following DNA damage caused by a wide variety of agents, including UV-irradiation (4, 5). wt p53 function has been shown to be required for activation of a G1 cell cycle checkpoint following ,y-irradiation (1, 2), presumably to facilitate efficient DNA repair prior to replication (6). For certain cell types, p53 may be required for DNA damage-induced apoptosis (3). Cells deficient in wt p53 function may fail to arrest in G1 or to induce cell elimination via apoptosis after DNA damage and thereby may attempt replication of a damaged genome. This model suggests that cells with mutant p53 will accumulate further mutations more rapidly and display increased genomic instability due to unrepaired damage, consistent with the increased neoplastic potential of patients with Li-Fraumeni syndrome (LFS), who inherit a germ-line defect in one p53 allele (7). It also predicts that loss or mutation of p53 may result in an alteration in cellular sensitivity to DNA-damaging agents due to loss of a p53-dependent apoptotic response.The effect of p53 mutations on DNA repair and cellular sensitivity to UV-irradiation has not been fully examined. Treatment of cells with UV-irradiation leads to increased wt p53 protein levels (4, 5) and sequence-specific DNA binding by p53 (8), resulting in transcriptional activation of the mdm2 gene (9), GADD45 gene (10), and the p53CIP1/wAF1 cyclindependent kinase inhibitor (11).Several lines of investigation have provided indirect evidence implicating p53 or proteins encoded downstream in a p53 damage-response pathway as affecting nucleotide excision ...

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“…The XPD gene that encodes a helicase, a subunit of transcription factor IIH (TFIIH), is responsible for opening DNA around the damaged site, a crucial step in initiating the NER process (Egly 2001), which repairs bulky adducts and UV-induced DNA damage (Weeda and Hoeijmakers 1993). Several XPD polymorphisms in the coding regions have been identiWed (Shen et al 1998), including two single nucleotide polymorphisms, Asp312Asn in exon 10 and Lys751Gln in exon 23.…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms in DNA repair genes XRCC1, XRCC3 and XPD, and colorectal cancer risk: a case–control study in an Indian population

Wang

Zhao

Jiang

et al. 2010

J Cancer Res Clin Oncol

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Genes controlling nucleotide excision repair in eukaryotic cells

Cited by 48 publications

References 53 publications

The Essential Helicase Gene RAD3 Suppresses Short-Sequence Recombination in Saccharomyces cerevisiae

The Essential Helicase Gene RAD3 Suppresses Short-Sequence Recombination in Saccharomyces cerevisiae

Li-Fraumeni syndrome fibroblasts homozygous for p53 mutations are deficient in global DNA repair but exhibit normal transcription-coupled repair and enhanced UV resistance.

Polymorphisms in DNA repair genes XRCC1, XRCC3 and XPD, and colorectal cancer risk: a case–control study in an Indian population

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