Co-transcriptional R-loops and their possible roles as genomic threats

Dysfunctional RNA processing has been linked to genome instability in a range of organisms. However, the mechanisms underlying genome destabilization under conditions of altered co-transcriptional RNA processing have not been fully elucidated. Here, I will provide an update on our investigations of the consequences of dysfunctional RNA splicing and RNA processing on patterns of nascent transcription, R-loop distributions, and DNA double-strand break mapping using several human cell culture models. Our work to date shows that splicing inhibition causes profound negative feedback on nascent transcription at several different steps and the induction of a global splicing shock stress response. The R-loop landscapes largely reflect these underlying transcriptional perturbations. The distribution of DNA breaks and the ability of Ribonuclease H1 to suppress the genome instability phenotypes, however, will be discussed. Overall, this work will help us define what defines “harmful” R-loops and whether and how they may be causally linked to genome destabilization events.