Transcription-coupled DNA repair without the transcription-coupling repair factor

Abstract

Repair of DNA damage by the versatile nucleotide excision repair (NER) pathway proceeds much faster in the transcribed strand of an active gene than it does in the non-transcribed strand or in the global genome. This transcription-coupled repair (TCR) was first described almost 15 years ago but, despite its obvious importance for maintenance of genome integrity, little has been learned about the molecular mechanisms that make such preferential repair possible. New results from the Brouwer laboratory 1xSpt4 modulates Rad26 requirement in transcription-coupled nucleotide excision repair. Jansen, L.T et al. EMBO J. 2000; 19: 6498–6507Crossref | PubMedSee all References1 now suggest that TCR works better when the efficiency of transcriptional elongation is relaxed.Two genes, Cockayne's Syndrome A (CSA) and B (CSB), encode proteins that are involved in this process. The yeast homologue of CSB is RAD26 and, like mammalian CS cells, rad26 cells show a markedly slower repair of the transcribed strand of an active gene than do normal cells. CSB and Rad26 are DNA-dependent ATPases often thought of as possible functional analogues of the bacterial transcription coupling repair factor (TCRF) protein, which interacts directly with the bacterial NER machinery and is capable of displacing a stalled RNA polymerase, thus enabling DNA repair. The new results 1xSpt4 modulates Rad26 requirement in transcription-coupled nucleotide excision repair. Jansen, L.T et al. EMBO J. 2000; 19: 6498–6507Crossref | PubMedSee all References1 show that in an active yeast gene, where TCR was previously shown to be completely dependent on RAD26, fast preferential repair of the transcribed strand can actually take place in the absence of RAD26, provided the SPT4 gene is also deleted. Spt4 and its partner Spt5 form a complex [DRB sensitivity-inducing factor (DSIF) in mammalian cells] that assists transcription elongation and interacts with RNA polymerase II. Genetic interactions between SPT4 and NER factors indicate an even closer relationship between transcriptional elongation and NER than previously described.These data suggest that, in contrast to TCRF, Rad26 (and, thereby in all likelihood, CSB) is not involved in the TCR reaction per se, and point to RNA polymerase II elongation complexes as important determinants for the efficiency of TCR. Different models to explain the possible role of Rad26 in TCR could be suggested. However, one simple interpretation is that, in the presence of DNA damage, efficient transcriptional elongation becomes counter-productive. During such adversity, Rad26 and CSB might help to prevent the RNA polymerase II elongation complexes from ‘choking’ on the damage. When Spt4 is missing from cells, transcription elongation efficiency might already be reduced, thus eliminating the need for Rad26 and CSB.