Cohesin Ubiquitylation and Mobilization Facilitate Stalled Replication Fork Dynamics

Camilla Frattini; Sara Villa-Hernández; Grazia Pellicanò; Rachel Jossen; Yuki Katou; Katsuhiko Shirahige; Rodrigo Bermejo

doi:10.1016/j.molcel.2017.10.012

Cohesin Ubiquitylation and Mobilization Facilitate Stalled Replication Fork Dynamics

Mol Cell. 2017 Nov 16;68(4):758-772.e4. doi: 10.1016/j.molcel.2017.10.012. Epub 2017 Nov 9.

Authors

Camilla Frattini¹, Sara Villa-Hernández¹, Grazia Pellicanò², Rachel Jossen³, Yuki Katou⁴, Katsuhiko Shirahige⁴, Rodrigo Bermejo⁵

Affiliations

¹ Instituto de Biología Funcional y Genómica (IBFG-CSIC), Universidad de Salamanca, Calle Zacarías González 2, 37007 Salamanca, Spain; Centro de Investigaciones Biológicas (CIB-CSIC), Calle Ramiro de Maeztu 9, 28040 Madrid, Spain.
² Centro de Investigaciones Biológicas (CIB-CSIC), Calle Ramiro de Maeztu 9, 28040 Madrid, Spain.
³ Instituto de Biología Funcional y Genómica (IBFG-CSIC), Universidad de Salamanca, Calle Zacarías González 2, 37007 Salamanca, Spain.
⁴ Laboratory of Genome Structure and Function, Research Center for Epigenetic Disease, Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi Bunkyo-Ku, Tokyo, Japan.
⁵ Instituto de Biología Funcional y Genómica (IBFG-CSIC), Universidad de Salamanca, Calle Zacarías González 2, 37007 Salamanca, Spain; Centro de Investigaciones Biológicas (CIB-CSIC), Calle Ramiro de Maeztu 9, 28040 Madrid, Spain. Electronic address: rodrigo.bermejo@csic.es.

PMID: 29129641
DOI: 10.1016/j.molcel.2017.10.012

Abstract

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 Rsp5^Bul2 ubiquitin ligase in promoting survival to replication stress by preserving stalled fork integrity. Rsp5^Bul2 physically interacts with cohesin and the Mec1 kinase, thus promoting checkpoint-dependent cohesin ubiquitylation and cohesin-mediated fork protection. Ubiquitylation mediated by Rsp5^Bul2 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 Rsp5^Bul2 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: Cdc148/p97; DNA replication; checkpoint; chromosome dynamics; cohesin; genome integrity; replication forks; replication stress.

MeSH terms

Acetyltransferases / genetics
Acetyltransferases / metabolism
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism*
Chromosomal Proteins, Non-Histone / genetics
Chromosomal Proteins, Non-Histone / metabolism*
Cohesins
DNA Replication / physiology*
DNA, Fungal / biosynthesis*
DNA, Fungal / genetics
Endosomal Sorting Complexes Required for Transport / genetics
Endosomal Sorting Complexes Required for Transport / metabolism
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism
Saccharomyces cerevisiae / genetics
Saccharomyces cerevisiae / metabolism*
Saccharomyces cerevisiae Proteins / genetics
Saccharomyces cerevisiae Proteins / metabolism
Ubiquitin-Protein Ligase Complexes / genetics
Ubiquitin-Protein Ligase Complexes / metabolism
Ubiquitination / physiology*
Valosin Containing Protein / genetics
Valosin Containing Protein / metabolism

Substances

Cell Cycle Proteins
Chromosomal Proteins, Non-Histone
DNA, Fungal
Endosomal Sorting Complexes Required for Transport
Intracellular Signaling Peptides and Proteins
Nuclear Proteins
RAD61 protein, S cerevisiae
Saccharomyces cerevisiae Proteins
Acetyltransferases
ECO1 protein, S cerevisiae
Ubiquitin-Protein Ligase Complexes
MEC1 protein, S cerevisiae
Protein Serine-Threonine Kinases
CDC48 protein, S cerevisiae
Valosin Containing Protein
RSP5 protein, S cerevisiae