RAD52 resolves transcription-replication conflicts to mitigate R-loop induced genome instability

Affiliations

• Department of Radiation Oncology, MSKCC, New York, NY, 10065, USA
• Department of Pathology and Laboratory Medicine, MSKCC, New York, NY, 10065, USA
• Human Oncology and Pathogenesis, MSKCC, New York, NY, 10065, USA
• Department for BioMedical Research, University of Bern, Bern, CH, 3008, Switzerland SIB, Swiss Institute of Bioinformatics, Lausanne, 1015, Switzerland
• Molecular Biology Program, MSKCC, New York, NY, 10065, USA

PMID:  #  DOI: 10.1038/s41467-024-51784-x

Abstract

Collisions of the transcription and replication machineries on the same DNA strand can pose a significant threat to genomic stability. These collisions occur in part due to the formation of RNA-DNA hybrids termed R-loops, in which a newly transcribed RNA molecule hybridizes with the DNA template strand. This study investigated the role of RAD52, a known DNA repair factor, in preventing collisions by directing R-loop formation and resolution. We show that RAD52 deficiency increases R-loop accumulation, exacerbating collisions and resulting in elevated DNA damage. Furthermore, RAD52’s ability to interact with the transcription machinery, coupled with its capacity to facilitate R-loop dissolution, highlights its role in preventing collisions. Lastly, we provide evidence of an increased mutational burden from double-strand breaks at conserved R-loop sites in human tumor samples, which is increased in tumors with low RAD52 expression. In summary, this study underscores the importance of RAD52 in orchestrating the balance between replication and transcription processes to prevent collisions and maintain genome stability.

在同一条DNA链上，转录和复制机制的冲突对基因组稳定性构成重大威胁。部分冲突是由于形成了RNA-DNA杂交体，称为R loop，其中新转录的RNA分子与DNA模板链杂合。本研究探讨了已知的DNA修复因子RAD52在预防冲突中的作用，RAD52通过引导R loop的形成和解决来防止冲突。我们发现，RAD52缺失会导致R loop积累，冲突恶化并导致DNA损伤增加。此外，RAD52与转录机制的相互作用及其促进R loop解散的能力，突显了其在预防冲突中的作用。最后，我们提供了证据，显示在RAD52表达水平低的肿瘤样本中，保守R loop位点的双链断裂导致突变负担增加。总之，本研究强调了RAD52在协调复制和转录过程中的重要性，以防止冲突并维持基因组稳定性。