Co-Essentiality Analysis Identifies PRR12 as a Regulator of Cohesin and Genome Integrity

The cohesin complex is critical for genome regulation, relying on specialized co-factors to mediate its diverse functional activities. Here, by analyzing patterns of similar gene requirements across cell lines, we identify PRR12 as a regulator of cohesin and genome integrity. We show that PRR12 interacts with cohesin and PRR12 loss results in a reduction of nuclear-localized cohesin and an accumulation of DNA lesions. We find that different cell lines across human and mouse exhibit significant variation in their sensitivity to PRR12 loss. Unlike the modest phenotypes observed in human cell lines, PRR12 depletion in mouse cells results in substantial genome instability. Despite a modest requirement in human cell lines, mutations in PRR12 lead to severe developmental defects in human patients, suggesting context-specific roles in cohesin regulation. By harnessing comparative studies across species and cell lines, our work reveals critical insights into how cohesin is regulated across diverse cellular contexts.