RAD52 resolves transcription-replication conflicts to mitigate R-loop induced genome instability
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.
Authors
- Kyrie S Anderson
- Melody Di Bona (ORCID: https://orcid.org/0000-0002-8853-2604)
- Pier Selenica (ORCID: https://orcid.org/0000-0003-0086-0513)
- Erika S. Buechelmaier (ORCID: https://orcid.org/0000-0002-7463-7536)
- Manisha Jalan (ORCID: https://orcid.org/0000-0002-4467-4934)
- Nadeem Riaz (ORCID: https://orcid.org/0000-0001-9873-5862)
- Samuel F. Bakhoum
- Simon N. Powell (ORCID: https://orcid.org/0000-0002-8183-4765)
- Charlotte K.Y. Ng (ORCID: https://orcid.org/0000-0002-6100-0026)
- Abhirami Ratnakumar (ORCID: https://orcid.org/0000-0001-9623-0377)
- Niamh McDermott (ORCID: https://orcid.org/0000-0001-6045-9364)
- Sana Ahmed‐Seghir
- Nils Weinhold (ORCID: https://orcid.org/0000-0003-3290-6192)
- Aman Sharma (ORCID: https://orcid.org/0000-0003-1017-8307)
- Yingjie Zhu (ORCID: https://orcid.org/0000-0003-1849-6019)
- Xin Pei (ORCID: https://orcid.org/0000-0001-9961-6152)
- Joan Gomez-Aguilar
- Jorge S. Reis-Filho
Institutions
- University of Bern (CH)
- SIB Swiss Institute of Bioinformatics (CH)
- Northwell Health (US)
- Bern University of Applied Sciences (CH)
- Motlow State Community College (US)
- Manhattan Scientifics (United States) (US)
- New York Oncology Hematology (US)
- AstraZeneca (United States) (US)
- Organogenesis (United States) (US)
- New York University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-05
- DOI
- https://doi.org/10.1038/s41467-024-51784-x
- Citations
- 15
- Primary Topic
- DNA Repair Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 3.51
Funders
- American Association for Cancer Research
- National Cancer Institute