Header

UZH-Logo

Maintenance Infos

A mechanism for controlled breakage of under-replicated chromosomes during mitosis


Duda, Heike; Arter, Meret; Gloggnitzer, Jiradet; Teloni, Federico; Wild, Philipp; Blanco, Miguel G; Altmeyer, Matthias; Matos, Joao (2016). A mechanism for controlled breakage of under-replicated chromosomes during mitosis. Developmental Cell, 39(6):740-755.

Abstract

While DNA replication and mitosis occur in a sequential manner, precisely how cells maintain their temporal separation and order remains elusive. Here, we unveil a double-negative feedback loop between replication intermediates and an M-phase-specific structure-selective endonuclease, MUS81-SLX4, which renders DNA replication and mitosis mutually exclusive. MUS81 nuclease is constitutively active throughout the cell cycle but requires association with SLX4 for efficient substrate targeting. To preclude toxic processing of replicating chromosomes, WEE1 kinase restrains CDK1 and PLK1-mediated MUS81-SLX4 assembly during S phase. Accordingly, WEE1 inhibition triggers widespread nucleolytic breakage of replication intermediates, halting DNA replication and leading to chromosome pulverization. Unexpectedly, premature entry into mitosis—licensed by unrestrained CDK1 activity during S phase—requires MUS81-SLX4, which inhibits DNA replication. This suggests that ongoing replication assists WEE1 in delaying entry into M phase and, indirectly, in preventing MUS81-SLX4 assembly. Conversely, MUS81-SLX4 activation during mitosis promotes targeted resolution of persistent replication intermediates, which safeguards chromosome segregation.

Abstract

While DNA replication and mitosis occur in a sequential manner, precisely how cells maintain their temporal separation and order remains elusive. Here, we unveil a double-negative feedback loop between replication intermediates and an M-phase-specific structure-selective endonuclease, MUS81-SLX4, which renders DNA replication and mitosis mutually exclusive. MUS81 nuclease is constitutively active throughout the cell cycle but requires association with SLX4 for efficient substrate targeting. To preclude toxic processing of replicating chromosomes, WEE1 kinase restrains CDK1 and PLK1-mediated MUS81-SLX4 assembly during S phase. Accordingly, WEE1 inhibition triggers widespread nucleolytic breakage of replication intermediates, halting DNA replication and leading to chromosome pulverization. Unexpectedly, premature entry into mitosis—licensed by unrestrained CDK1 activity during S phase—requires MUS81-SLX4, which inhibits DNA replication. This suggests that ongoing replication assists WEE1 in delaying entry into M phase and, indirectly, in preventing MUS81-SLX4 assembly. Conversely, MUS81-SLX4 activation during mitosis promotes targeted resolution of persistent replication intermediates, which safeguards chromosome segregation.

Statistics

Citations

Dimensions.ai Metrics
36 citations in Web of Science®
29 citations in Scopus®
10 citations in Microsoft Academic
Google Scholar™

Altmetrics

Downloads

24 downloads since deposited on 16 Jan 2017
18 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:05 Vetsuisse Faculty > Department of Molecular Mechanisms of Disease
07 Faculty of Science > Department of Molecular Mechanisms of Disease
Dewey Decimal Classification:570 Life sciences; biology
Scopus Subject Areas:Life Sciences > Molecular Biology
Life Sciences > General Biochemistry, Genetics and Molecular Biology
Life Sciences > Developmental Biology
Life Sciences > Cell Biology
Language:English
Date:2016
Deposited On:16 Jan 2017 14:08
Last Modified:01 Apr 2020 22:09
Publisher:Cell Press (Elsevier)
ISSN:1534-5807
OA Status:Green
Publisher DOI:https://doi.org/10.1016/j.devcel.2016.11.017
PubMed ID:27997828
Project Information:
  • : FunderSNSF
  • : Grant IDBSSGI0_155823
  • : Project TitleRewiring the DNA repair machinery for genome stability and haploidisation
  • : FunderSNSF
  • : Grant ID31003A_153058
  • : Project TitleCoordination of DNA repair and segregation during meiosis and mitosis
  • : FunderSNSF
  • : Grant IDPP00P3_150690
  • : Project TitleUncovering concealed regulators and unexpected pathway connections guarding against genome instability

Download

Green Open Access

Download PDF  'A mechanism for controlled breakage of under-replicated chromosomes during mitosis'.
Preview
Content: Accepted Version
Filetype: PDF
Size: 41MB
Licence: Creative Commons: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)