Cohesin is an essential multiprotein complex that mediates sister chromatid cohesion critical for proper segregation of chromosomes during cell division. Cohesin is also involved in DNA double-strand break (DSB) repair. In mammalian cells, cohesin is involved in both DSB repair and the damage checkpoint response, although the relationship between these two functions is unclear. Two cohesins differing by one subunit (SA1 or SA2) are present in somatic cells, but their functional specificities with regard to DNA repair remain enigmatic. We found that cohesin-SA2 is the main complex corecruited with the cohesin-loading factor NIPBL to DNA damage sites in an S/G 2 -phase-specific manner. Replacing the diverged C-terminal region of SA1 with the corresponding region of SA2 confers this activity on SA1. Depletion of SA2 but not SA1 decreased sister chromatid homologous recombination repair and affected repair pathway choice, indicating that DNA repair activity is specifically associated with cohesin recruited to damage sites. In contrast, both cohesin complexes function in the intra-S checkpoint, indicating that cell cyclespecific damage site accumulation is not a prerequisite for cohesin's intra-S checkpoint function. Our findings reveal the unique ways in which cohesin-SA1 and cohesin-SA2 participate in the DNA damage response, coordinately protecting genome integrity in human cells. DNA double-strand breaks (DSBs) are deleterious to genome integrity and can result in chromosomal breakage or translocations and cell death. The two major mechanisms to repair DSBs are the error-prone nonhomologous end joining (NHEJ) and the error-free homologous-recombination (HR) pathways, which involve distinct sets of repair proteins (1). While NHEJ operates throughout the cell cycle, HR utilizes an intact sister chromatid as a repair template and thus is restricted to S/G 2 phase in mammalian cells. Although the two pathways complement one another, the error-free HR pathway is particularly important for accurate damage repair. DSBs also evoke DNA damage checkpoint responses that are mediated by ATM (and the related ATR) (1-3). The G 1 /S and G 2 /M checkpoints, which inhibit cell cycle progression, and the intra-S checkpoint, which inhibits DNA replication, together provide adequate time for DNA repair. Both the checkpoint and the repair functions coordinately maintain genome integrity and stability.The primary function of cohesin is to mediate genome-wide sister chromatid cohesion in a cell cycle-regulated manner to ensure proper segregation of chromosomes in mitosis (4-8). Cohesin contains two SMC proteins (SMC1 and SMC3) and the two non-SMC subunits Rad21 (Scc1) and SA (Scc3 or STAG). Whereas a single Scc3 is present in yeast, two SA proteins, SA1 and SA2, are found in higher eukaryotes that form two distinct cohesin complexes in somatic cells: cohesin-SA1 and cohesin-SA2 (9, 10). Both cohesin-SA1 and cohesin-SA2 contribute to genome-wide sister chromatid cohesion, although SA1 is particularly important for telomeric sister chrom...

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