Nucleotide Excision Repair, Genome Stability, and Human Disease: New Insight from Model Systems

BioMed Research International (Impact Factor: 2.71). 02/2002; 2(2). DOI: 10.1155/S1110724302201023
Source: DOAJ

ABSTRACT

Nucleotide excision repair (NER) is one of several DNA repair pathways that are universal throughout phylogeny. NER has a broad
substrate specificity and is capable of removing several classes of lesions to the DNA, including those that accumulate upon exposure to UV radiation. The loss of this activity in NER-defective mutants gives rise to characteristic sensitivities to UV that, in humans, is manifested as a greatly elevated sensitivity to exposure to the sun. Xeroderma pigmentosum (XP),
Cockaynes syndrome (CS), and trichothiodystrophy (TTD) are three, rare, recessively inherited human diseases that are linked to these defects. Interestingly, some of the symptoms in afflicted individuals appear to be due to defects in transcription, the result of the dual functionality of several components of the NER apparatus as parts of transcription factor
IIH (TFIIH). Studies with several model systems have revealed that the genetic and biochemical features of NER are extraordinarily conserved in eukaryotes. One system that has been studied very closely is the budding yeast Saccharomyces cerevisiae. While many yeast NER mutants display the expected increases in UV sensitivity and defective transcription, other interesting phenotypes have also been observed. Elevated mutation and recombination rates, as well as increased frequencies of genome rearrangement by retrotransposon movement and recombination between short genomic sequences have been documented. The potential relevance of these novel phenotypes to disease in humans is discussed.

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    • "During this process, regions of DNA containing the CPD are excised along with adjacent nucleotides and replaced by newly synthesized DNA. At least 20–30 proteins are involved in the pathway in a sequential manner (Garfinkel and Bailis, 2002). Corals have been shown to be greatly impaired by UV exposure when placed in the dark following UV irradiation, implying a significant role for photoreactivation repair (Siebeck, 1981). "
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    • "Mutant alleles of the RAD3, SSL1, and SSL2 genes confer several genetically separable phenotypes, indicative of their roles in multiple cellular functions. Consistent with these observations, human homologs of these genes have been linked to the diseases xeroderma pigmentosum, Cockayne's syndrome, and trichothiodystrophy , which are characterized by transcriptional and DNA repair defects and increased tumor formation (Garfinkel and Bailis 2002). While mutations in the yeast RAD3 and SSL1 genes create separable transcription , NER, and recombination phenotypes (Montelone et al. 1988; Song et al. 1990; Feaver et al. 1993; Montelone and Malone 1994; Wang et al. 1995; Maines et al. 1998), it remains unclear how these changes are related. "
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    ABSTRACT: Increased mitotic recombination enhances the risk for loss of heterozygosity, which contributes to the generation of cancer in humans. Defective DNA replication can result in elevated levels of recombination as well as mutagenesis and chromosome loss. In the yeast Saccharomyces cerevisiae, a null allele of the RAD27 gene, which encodes a structure-specific nuclease involved in Okazaki fragment processing, stimulates mutation and homologous recombination. Similarly, rad3-102, an allele of the gene RAD3, which encodes an essential helicase subunit of the core TFIIH transcription initiation and DNA repairosome complexes confers a hyper-recombinagenic and hypermutagenic phenotype. Combining the rad27 null allele with rad3-102 dramatically stimulated interhomolog recombination and chromosome loss but did not affect unequal sister-chromatid recombination, direct-repeat recombination, or mutation. Interestingly, the percentage of cells with Rad52-YFP foci also increased in the double-mutant haploids, suggesting that rad3-102 may increase lesions that elicit a response by the recombination machinery or, alternatively, stabilize recombinagenic lesions generated by DNA replication failure. This net increase in lesions led to a synthetic growth defect in haploids that is relieved in diploids, consistent with rad3-102 stimulating the generation and rescue of collapsed replication forks by recombination between homologs.
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