Transcription-Coupled and Global Genome Nucleotide Excision Repair

Nucleotide excision repair (NER) is the main process used by cells to remove bulky lesions from DNA (reviewed in Friedberg et al. 1995). The molecular details of its mechanism have become increasingly clear during the past few years, and NER appears to be remarkably conserved during evolution from yeast to man. The role of the proteins involved has been studied at the biochemical level and eukaryotic NER has been reconstituted in highly purified in vitro systems (Aboussekhra et al. 1995; Guzder et al. 1995; Mu et al. 1995). In yeast, the Rad1/10 and Rad2 endonucleases, the Rad4/23 complex, the trimeric Rpa protein, the Rad14 DNA-damage recognizing protein, and the transcription/NER complex TFIIH are all necessary and sufficient for incision of damaged DNA (Guzder et al. 1995). These proteins will be referred to as the core NER proteins. Although all nucleotide excision repair appears to require at least this set of proteins, additional factors may be involved in vivo. The kinetics of removal of cyclobutane pyrimidine dimers (CPDs), the major lesions induced by UV-light, are not equal for all DNA in the cell: transcribed strands are repaired faster than non-transcribed DNA. We will discuss recent advances that give insight into the mechanism behind this observation, termed differential repair, leading to the hypothesis that differential repair is due to the operation of two subpathways of NER: transcriptioncoupled and global genome repair. The genes that are implicated in these subpathways in yeast and mammalian cells will be discussed.