A Mechanism for Controlled Breakage of Under-replicated Chromosomes during Mitosis

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, wh...

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Vydáno v:Developmental cell Ročník 39; číslo 6; s. 740 - 755
Hlavní autoři: Duda, Heike, Arter, Meret, Gloggnitzer, Jiradet, Teloni, Federico, Wild, Philipp, Blanco, Miguel G, Altmeyer, Matthias, Matos, Joao
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 19.12.2016
Témata:
CDC2 Protein Kinase - metabolism
Cell Cycle Proteins - metabolism
Cell Death
Cell Survival
Chromosomes, Human - metabolism
DNA Damage
DNA Fragmentation
DNA Replication
DNA-Binding Proteins - metabolism
Endonucleases - metabolism
HeLa Cells
Humans
Mitosis
Models, Biological
Phosphorylation
Protein Binding
Recombinases - metabolism
S Phase
MUS81
DNA replication
WEE1
SLX4
EME2
cell cycle
PLK1
chromosome pulverization
CDK1
ISSN:1878-1551
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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.
AbstractList 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.
Author Matos, Joao
Gloggnitzer, Jiradet
Duda, Heike
Blanco, Miguel G
Teloni, Federico
Arter, Meret
Wild, Philipp
Altmeyer, Matthias
Author_xml – sequence: 1
  givenname: Heike
  surname: Duda
  fullname: Duda, Heike
  organization: Institute of Biochemistry, ETH Zürich, Otto-Stern-Weg 3, 8093 Zürich, Switzerland
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  givenname: Meret
  surname: Arter
  fullname: Arter, Meret
  organization: Institute of Biochemistry, ETH Zürich, Otto-Stern-Weg 3, 8093 Zürich, Switzerland
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  givenname: Jiradet
  surname: Gloggnitzer
  fullname: Gloggnitzer, Jiradet
  organization: Institute of Biochemistry, ETH Zürich, Otto-Stern-Weg 3, 8093 Zürich, Switzerland
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  givenname: Federico
  surname: Teloni
  fullname: Teloni, Federico
  organization: Department of Molecular Mechanisms of Disease, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland
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  surname: Wild
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  organization: Institute of Biochemistry, ETH Zürich, Otto-Stern-Weg 3, 8093 Zürich, Switzerland
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  givenname: Miguel G
  surname: Blanco
  fullname: Blanco, Miguel G
  organization: Departamento de Bioquímica e Bioloxía Molecular, CIMUS, Universidade de Santiago de Compostela, Avda. de Barcelona, 15706 Santiago de Compostela, Spain
– sequence: 7
  givenname: Matthias
  surname: Altmeyer
  fullname: Altmeyer, Matthias
  organization: Department of Molecular Mechanisms of Disease, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland
– sequence: 8
  givenname: Joao
  surname: Matos
  fullname: Matos, Joao
  email: joao.matos@bc.biol.ethz.ch
  organization: Institute of Biochemistry, ETH Zürich, Otto-Stern-Weg 3, 8093 Zürich, Switzerland. Electronic address: joao.matos@bc.biol.ethz.ch
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ContentType Journal Article
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Issue 6
Keywords MUS81
DNA replication
WEE1
SLX4
EME2
cell cycle
PLK1
chromosome pulverization
CDK1
Language English
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SubjectTerms CDC2 Protein Kinase - metabolism
Cell Cycle Proteins - metabolism
Cell Death
Cell Survival
Chromosomes, Human - metabolism
DNA Damage
DNA Fragmentation
DNA Replication
DNA-Binding Proteins - metabolism
Endonucleases - metabolism
HeLa Cells
Humans
Mitosis
Models, Biological
Phosphorylation
Protein Binding
Recombinases - metabolism
S Phase
Title A Mechanism for Controlled Breakage of Under-replicated Chromosomes during Mitosis
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