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

Manisha Jalan,Aman Sharma,Xin Pei,Nils Weinhold,Erika S. Buechelmaier,Yingjie Zhu,Sana Ahmed-Seghir,A. Ratnakumar,M. Di Bona,Niamh McDermott,Joan Gomez-Aguilar,Kyrie S Anderson,C. Ng,P. Selenica,S. Bakhoum,J. Reis-Filho,N. Riaz,S. Powell

Published 2024 in Nature Communications

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. Collisions of transcription and replication machineries on the same DNA strand threaten genomic stability. Here, the authors show that RAD52 prevents these collisions by regulating R-loop formation and resolution. RAD52 deficiency leads to increased R-loops, exacerbated collisions, DNA damage, and higher mutational burden in tumors.

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