Mechanisms of transcription-coupled DNA repair

Abstract

Transcription-coupled repair (TCR) — the fast, preferential repair of the transcribed strand of an active gene — occurs in both prokaryotes and eukaryotes. This kind of repair is performed by the nucleotide excision repair (NER) or the base excision repair (BER) pathways. Different factors allow the repair machinery to be specifically targetted to the transcribed strand and the global genome, respectively. The best-studied TCR factors are CSA and CSB (yeast Rad26), but factors such as XPG and TFIIH also have a role. Cells respond to DNA damage by globally downregulating transcription. This might be brought about by several mechanisms working concomitantly. TCR is triggered by the stalled polymerase itself. In the promoter of an active gene, repair is slow. TCR is extra fast immediately downstream from the transcription initiation site, presumably because TFIIH is still associated with the polymerase at this point. Nucleosomes are inhibitory to NER on the non-transcribed strand (repair being slower towards the cores), whereas the speed of TCR is not affected by the presence of the same nucleosomes. In the transcribed strand, RNA polymerase II (RNAPII) is an obstacle to TCR and Rad26/CSB is required to overcome this obstacle to fast repair. Several models for the mechanism of TCR have been proposed, and they all incorporate some sort of displacement of RNAPII from the site of DNA damage. Although much has been learned about the factors and processes affecting TCR, much still needs to be learned about the precise molecular mechanism of the reaction.