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.
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