Cohesin Ubiquitylation and Mobilisation by an Rsp5/bul2 - cdc48axis facilitate stalled fork dynamics and integrity

Resumen

Replication fork stability is challenged in conditions of replication stress and protected by the Mec1/ATR checkpoint to preserve genome integrity. An enigmatic role in fork protection is played by cohesin, which mediates key chromosome transactions by topologically entrapping DNA. Searching for factors interfacing with the checkpoint response, we found that the Rsp5Bul2 ubiquitin ligase promotes stalled fork progression. Rsp5Bul2 physically interacts with cohesin and the Mec1 kinase, thus mediating checkpoint-dependent cohesin ubiquitylation and stimulating cohesin function in fork protection. The Cdc48/p97 ubiquitin selective segregase, together with Rsp5Bul2, promotes cohesin dissociation from replicating chromatin. Mobilization by Cdc48 involves Wpl1 function and is required for cohesin relocation to newly synthesized chromatids and replication stress survival. Cohesin-mediated fork protection also relies on Eco1, which secures sister chromatid entrapment. The results here presented indicate that ubiquitylation facilitates cohesin interfacing with stalled forks to protect fork-replisome dynamic architecture and sustain replication progression.