A dual role of Cohesin in DNA DSB repair

Michael Fedkenheuer (), Yafang Shang, Seolkyoung Jung, Kevin Fedkenheuer, Solji Park, Davide Mazza, Robin Sebastian, Hiroyuki Nagashima, Dali Zong, Hua Tan, Sushil Kumar Jaiswal, Haiqing Fu, Anthony Cruz, Supriya V. Vartak, Jan Wisniewski, Vittorio Sartorelli, John J. O’Shea, Laura Elnitski, Andre Nussenzweig, Mirit I. Aladjem, Fei-Long Meng and Rafael Casellas
Additional contact information
Michael Fedkenheuer: National Institutes of Health
Yafang Shang: University of Chinese Academy of Sciences
Seolkyoung Jung: National Institutes of Health
Kevin Fedkenheuer: National Institutes of Health
Solji Park: National Institutes of Health
Davide Mazza: Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute
Robin Sebastian: NIH
Hiroyuki Nagashima: National Institutes of Health
Dali Zong: National Cancer Institute NIH
Hua Tan: National Institutes of Health
Sushil Kumar Jaiswal: National Institutes of Health
Haiqing Fu: NIH
Anthony Cruz: National Institutes of Health
Supriya V. Vartak: National Institutes of Health
Jan Wisniewski: National Cancer Institute NIH
Vittorio Sartorelli: National Institutes of Health
John J. O’Shea: National Institutes of Health
Laura Elnitski: National Institutes of Health
Andre Nussenzweig: National Cancer Institute NIH
Mirit I. Aladjem: NIH
Fei-Long Meng: University of Chinese Academy of Sciences
Rafael Casellas: The University of Texas MD Anderson Cancer Center

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: Abstract Cells undergo tens of thousands of DNA-damaging events each day. Defects in repairing double-stranded breaks (DSBs) can lead to genomic instability, contributing to cancer, genetic disorders, immunological diseases, and developmental defects. Cohesin, a multi-subunit protein complex, plays a crucial role in both chromosome organization and DNA repair by creating architectural loops through chromatin extrusion. However, the mechanisms by which cohesin regulates these distinct processes are not fully understood. In this study, we identify two separate roles for cohesin in DNA repair within mammalian cells. First, cohesin serves as an intrinsic architectural factor that normally prevents interactions between damaged chromatin. Second, cohesin has an architecture-independent role triggered by ATM phosphorylation of SMC1, which enhances the efficiency of repair. Our findings suggest that these two functions work together to reduce the occurrence of translocations and deletions associated with non-homologous end joining, thereby maintaining genomic stability.

Date: 2025
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DOI: 10.1038/s41467-025-56086-4

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