Molecular Cell
Volume 68, Issue 4, 16 November 2017, Pages 758-772.e4
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Article
Cohesin Ubiquitylation and Mobilization Facilitate Stalled Replication Fork Dynamics

https://doi.org/10.1016/j.molcel.2017.10.012Get rights and content
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Highlights

  • Rsp5Bul2 modulates cohesin function to stabilize stalled replication forks

  • Cohesin is ubiquitylated in an Rsp5Bul2- and Mec1(ATR)-dependent manner

  • Rsp5Bul2 and Cdc48 mediate cohesin translocation to nascent chromatids

  • Nascent chromatid entrapment by cohesin promotes fork integrity

Summary

Replication fork integrity is challenged in conditions of stress and protected by the Mec1/ATR checkpoint to preserve genome stability. Still poorly understood in fork protection is the role played by the structural maintenance of chromosomes (SMC) cohesin complex. We uncovered a role for the Rsp5Bul2 ubiquitin ligase in promoting survival to replication stress by preserving stalled fork integrity. Rsp5Bul2 physically interacts with cohesin and the Mec1 kinase, thus promoting checkpoint-dependent cohesin ubiquitylation and cohesin-mediated fork protection. Ubiquitylation mediated by Rsp5Bul2 promotes cohesin mobilization from chromatin neighboring stalled forks, likely by stimulating the Cdc48/p97 ubiquitin-selective segregase, and its timely association to nascent chromatids. This Rsp5Bul2 fork protection mechanism requires the Wpl1 cohesin mobilizer as well as the function of the Eco1 acetyltransferase securing sister chromatid entrapment. Our data indicate that ubiquitylation facilitates cohesin dynamic interfacing with replication forks within a mechanism preserving stalled-fork functional architecture.

Keywords

cohesin
replication forks
DNA replication
checkpoint
replication stress
Cdc148/p97
chromosome dynamics
genome integrity

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These authors contributed equally

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