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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