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

[摘要] Nucleotide excision repair (NER) is one of several DNA repairpathways that are universal throughout phylogeny. NER has a broadsubstrate specificity and is capable of removing several classesof lesions to the DNA, including those that accumulate uponexposure to UV radiation. The loss of this activity inNER-defective mutants gives rise to characteristic sensitivitiesto UV that, in humans, is manifested as a greatly elevatedsensitivity to exposure to the sun. Xeroderma pigmentosum (XP),Cockayne’s syndrome (CS), and trichothiodystrophy (TTD) arethree, rare, recessively inherited human diseases that are linkedto these defects. Interestingly, some of the symptoms inafflicted individuals appear to be due to defects intranscription, the result of the dual functionality of severalcomponents of the NER apparatus as parts of transcription factorIIH (TFIIH). Studies with several model systems have revealedthat the genetic and biochemical features of NER areextraordinarily conserved in eukaryotes. One system that has beenstudied very closely is the budding yeastSaccharomycescerevisiae. While many yeast NER mutants display the expectedincreases in UV sensitivity and defective transcription, otherinteresting phenotypes have also been observed. Elevated mutationand recombination rates, as well as increased frequencies ofgenome rearrangement by retrotransposon movement andrecombination between short genomic sequences have beendocumented. The potential relevance of these novel phenotypes todisease in humans is discussed.

[学科分类] 基础医学