Transcription as a source of genome instability

Abstract

Transcription is associated with elevated recombination and mutagenesis in bacteria and in eukaryotes and thereby alters the genetic landscape. Concurrent transcription and replication of the same DNA template result in conflicts that lead to elevated chromosome fragility and recombination. In general, head-on collisions between the two machineries are more detrimental than co-directional collisions. The formation of stable hybrids between the nascent RNA and its DNA template (R-loops) destabilizes the underlying template. Rapid engagement of the RNA discourages R-loop formation, but if formed, R-loops can be removed by RNase H or RNA–DNA helicases. Transcription generates twin domains of positive and negative supercoiling, which are removed by topoisomerase 1 (Top1). The persistence of negative supercoils promotes R-loop formation. Transcription facilitates the formation of non-B-DNA structures, which have been implicated in human trinucleotide repeat diseases. Active genes suffer more DNA damage than inactive genes in bacteria and yeast, and damage preferentially accumulates on the non-transcribed strand. When DNA repair mechanisms are intact, most transcription-associated mutations in yeast are due to the activity of Top1. Transcription in yeast can alter the base composition of the underlying DNA template, and uracil specifically replaces thymine.