What causes an RNA-DNA hybrid to compromise genome integrity?

Transcription is a source of genome instability that stimulates mutation and recombination. Part of the damage produced by transcription is mediated by R-loops, non-B DNA structures that normally form by the re-annealing of the nascent RNA with the template DNA outside the catalytic center of the RNA polymerase, displacing the non-template strand. Recent discoveries have revealed that R-loops might not be harmful by themselves. Instead, chromatin compaction triggered by these structures seems necessary, as deduced from the histone modifications frequently found associated with harmful R-loops. Remarkably, hybrids may also become harmful if stabilized by specific RNA binding proteins, one example of which is the yeast Yra1. We discuss here the possible mechanisms by which cells may stabilize R-loops and the consequences on transcription-replication conflicts and telomere homeostasis.