Break‐induced RNA–DNA hybrids (BIRDHs) in homologous recombination: friend or foe?

Abstract

AbstractDouble‐strand breaks (DSBs) are the most harmful DNA lesions, with a strong impact on cell proliferation and genome integrity. Depending on cell cycle stage, DSBs are preferentially repaired by non‐homologous end joining or homologous recombination (HR). In recent years, numerous reports have revealed that DSBs enhance DNA–RNA hybrid formation around the break site. We call these hybrids “break‐induced RNA–DNA hybrids” (BIRDHs) to differentiate them from sporadic R‐loops consisting of DNA–RNA hybrids and a displaced single‐strand DNA occurring co‐transcriptionally in intact DNA. Here, we review and discuss the most relevant data about BIRDHs, with a focus on two main questions raised: (i) whether BIRDHs form by de novo transcription after a DSB or by a pre‐existing nascent RNA in DNA regions undergoing transcription and (ii) whether they have a positive role in HR or are just obstacles to HR accidentally generated as an intrinsic risk of transcription. We aim to provide a comprehensive view of the exciting and yet unresolved questions about the source and impact of BIRDHs in the cell.