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

Autor: Jalan M; Department of Radiation Oncology, MSKCC, New York, NY, 10065, USA. jalanm@mskcc.org., Sharma A; Department of Radiation Oncology, MSKCC, New York, NY, 10065, USA., Pei X; Department of Radiation Oncology, MSKCC, New York, NY, 10065, USA., Weinhold N; Department of Radiation Oncology, MSKCC, New York, NY, 10065, USA., Buechelmaier ES; Department of Radiation Oncology, MSKCC, New York, NY, 10065, USA., Zhu Y; Department of Pathology and Laboratory Medicine, MSKCC, New York, NY, 10065, USA., Ahmed-Seghir S; Department of Radiation Oncology, MSKCC, New York, NY, 10065, USA., Ratnakumar A; Department of Radiation Oncology, MSKCC, New York, NY, 10065, USA., Di Bona M; Department of Radiation Oncology, MSKCC, New York, NY, 10065, USA.; Human Oncology and Pathogenesis, MSKCC, New York, NY, 10065, USA., McDermott N; Department of Radiation Oncology, MSKCC, New York, NY, 10065, USA., Gomez-Aguilar J; Department of Radiation Oncology, MSKCC, New York, NY, 10065, USA., Anderson KS; Department of Radiation Oncology, MSKCC, New York, NY, 10065, USA., Ng CKY; Department for BioMedical Research, University of Bern, Bern, CH, 3008, Switzerland.; SIB, Swiss Institute of Bioinformatics, Lausanne, 1015, Switzerland., Selenica P; Department of Pathology and Laboratory Medicine, MSKCC, New York, NY, 10065, USA., Bakhoum SF; Department of Radiation Oncology, MSKCC, New York, NY, 10065, USA.; Human Oncology and Pathogenesis, MSKCC, New York, NY, 10065, USA., Reis-Filho JS; Department of Pathology and Laboratory Medicine, MSKCC, New York, NY, 10065, USA.; AstraZeneca, Gaithersburg, MD, 20878, USA., Riaz N; Department of Radiation Oncology, MSKCC, New York, NY, 10065, USA., Powell SN; Department of Radiation Oncology, MSKCC, New York, NY, 10065, USA. powells@mskcc.org.; Molecular Biology Program, MSKCC, New York, NY, 10065, USA. powells@mskcc.org.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Sep 05; Vol. 15 (1), pp. 7776. Date of Electronic Publication: 2024 Sep 05.
DOI: 10.1038/s41467-024-51784-x
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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