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Significance The cohesin complex both tethers together sister chromatids following DNA replication and ensures chromosome compaction and proper gene expression throughout interphase by folding chromosomes into loops and domains. How these very different activities of cohesin are controlled is largely unknown. The ESCO2 acetyltransferase modifies the SMC3 subunit of cohesin and is uniquely able to promote cohesion between sister chromatids, while the related ESCO1 acetyltransferase, which has the same catalytic activity, does not. Here we show that ESCO2 interacts with the DNA replication machinery through several highly conserved sequences in its unstructured tail. These interactions ensure that cohesin is modified precisely when sister chromatids are formed. This work provides a model to understand how cohesin activity is entrained to specific contexts.

Multivalent interaction of ESCO2 with the replication machinery is required for sister chromatid cohesion in vertebrates