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

Abstract

Double‐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.

Local Genomic Instability of the SpTransformer Gene Family in the Purple Sea Urchin Inferred from BAC Insert Deletions

“…DNA damage resulting in local genomic instability includes (i) DNA replication stress at fragile sites composed of STRs and other types of repeats [6], (ii) R loops of DNA-RNA hybrids that can lead to double-strand breaks [81,82] and double-strand breaks that occur during general DNA replication (reviewed in [83,84], (iii) highly expressed genomic regions resulting in DNA damage from transcription-replication conflicts [85,86], and (vi) DNA tangles resolved by cleavage followed by incorrect re-ligation [87]. DNA damage and genomic instability are counteracted by DNA repair mechanisms and expression in response to DNA damage in eukaryotes [88].…”

RNA biogenesis and RNA metabolism factors as R-loop suppressors: a hidden role in genome integrity

“…1 ), as originally reported in different studies ( Roy et al 2010 ; Britton et al 2014 ; Ohle et al 2016 ). Some reports suggest that BIRDHs may help the repair of DSBs, whereas others suggest that they are a cotranscriptional accidental event (for review, see Gómez-González and Aguilera 2023 ). Either way, it seems clear that BIRDHs must be removed for DSB repair completion.…”

“…In the last two decades, research on R-loops and DNA–RNA hybrids has increased exponentially ( Li et al 2023 ), and numerous general reviews on the origin and consequences of R-loops have been published recently ( García-Muse and Aguilera 2019 ; Niehrs and Luke 2020 ; Chédin et al 2021 ; Marnef and Legube 2021 ; Brickner et al 2022 ; Cerritelli et al 2022 ; Petermann et al 2022 ; Gómez-González and Aguilera 2023 ). The specific role of DNA–RNA hybrids as intermediates in gene editing by CRISPR has also been reviewed ( Jiang and Doudna 2017 ).…”