Induced degradation of Ufd1 reveals regulation of cohesin by the VCP/p97 Ufd1-Npl4 complex

The AAA ATPase VCP/p97 has emerged as a critical regulator of ubiquitin and chromatin-associated processes but progress in understanding has been hampered by the complexity of p97 functions and the various p97 cofactors involved. Here, we combined ubiquitin profiling with acutely induced degradation of the Ufd1 subunit of the p97 ubiquitin adapter, Ufd1-Npl4, in human cells. We identified a set of chromatin regulators, HUS1, XRCC1, MORF4L1, and the cohesin subunit RAD21 as targets of p97 Ufd1-Npl4 . We find that RAD21 is ubiquitylated and targeted by p97 Ufd1-Npl4 specifically in S phase to remove a subpopulation of cohesin from chromatin. Acute degradation of Ufd1 in S phase, after replication licensing is completed, impedes replication and leads to replication-associated DNA damage. Our findings suggest that a fraction of cohesin rings need to be removed by p97 Ufd1-Npl4 from DNA to allow unhindered replication and reveal a critical function of p97 that ensures genome stability.