Slx5/Slx8 Promotes Replication Stress Tolerance by Facilitating Mitotic Progression

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19 Scopus citations

Abstract

Loss of minichromosome maintenance protein 10 (Mcm10) causes replication stress. We uncovered that S. cerevisiae mcm10-1 mutants rely on the E3 SUMO ligase Mms21 and the SUMO-targeted ubiquitin ligase complex Slx5/8 for survival. Using quantitative mass spectrometry, we identified changes in the SUMO proteome of mcm10-1 mutants and revealed candidates regulated by Slx5/8. Such candidates included subunits of the chromosome passenger complex (CPC), Bir1 and Sli15, known to facilitate spindle assembly checkpoint (SAC) activation. We show here that Slx5 counteracts SAC activation in mcm10-1 mutants under conditions of moderate replication stress. This coincides with the proteasomal degradation of sumoylated Bir1. Importantly, Slx5-dependent mitotic relief was triggered not only by Mcm10 deficiency but also by treatment with low doses of the alkylating drug methyl methanesulfonate. Based on these findings, we propose a model in which Slx5/8 allows for passage through mitosis when replication stress is tolerable.

Original languageEnglish (US)
Pages (from-to)1254-1265
Number of pages12
JournalCell reports
Volume15
Issue number6
DOIs
StatePublished - May 10 2016

Bibliographical note

Funding Information:
We thank members of the A.K.B. laboratory for helpful discussions and Eric Hendrickson for critical reading of the manuscript. We also thank B. Stillman, X. Zhao, J.F.X. Diffley, G. Brush, M. Hochstrasser, and D. Moazed for generously sharing their reagents. We wish to acknowledge the University of Minnesota Flow Cytometry Resource and the Minnesota Supercomputing Institute. This work was supported by NIH grant GM074917 (A.K.B.) and partly through a scholarship by the Leukemia & Lymphoma Society LLS1023-09 (A.K.B.). The authors recognize the Center for Mass Spectrometry and Proteomics at the University of Minnesota.

Publisher Copyright:
© 2016 The Authors.

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