Mitotic CDK Promotes Replisome Disassembly, Fork Breakage, and Complex DNA Rearrangements

Lin Deng, R. Alex Wu, Remi Sonneville, Olga V. Kochenova, Karim Labib, David Pellman (Lead / Corresponding author), Johannes C. Walter (Lead / Corresponding author)

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

DNA replication errors generate complex chromosomal rearrangements and thereby contribute to tumorigenesis and other human diseases. One mechanism that triggers these errors is mitotic entry before the completion of DNA replication. To address how mitosis might affect DNA replication, we used Xenopus egg extracts. When mitotic CDK (Cyclin B1-CDK1) is used to drive interphase egg extracts into a mitotic state, the replicative CMG (CDC45/MCM2-7/GINS) helicase undergoes ubiquitylation on its MCM7 subunit, dependent on the E3 ubiquitin ligase TRAIP. Whether replisomes have stalled or undergone termination, CMG ubiquitylation is followed by its extraction from chromatin by the CDC48/p97 ATPase. TRAIP-dependent CMG unloading during mitosis is also seen in C. elegans early embryos. At stalled forks, CMG removal results in fork breakage and end joining events involving deletions and templated insertions. Our results identify a mitotic pathway of global replisome disassembly that can trigger replication fork collapse and DNA rearrangements. Mitotic entry before completion of DNA replication causes genome instability via an unknown mechanism. Using Xenopus egg extracts, Deng et al. find that mitotic cyclin-dependent kinase triggers replication fork breakage and DNA rearrangements. The mechanism requires TRAIP-dependent ubiquitylation of the replicative helicase followed by p97 ATPase-dependent helicase removal from chromatin.

Original languageEnglish
Pages (from-to)915-929.e6
Number of pages22
JournalMolecular Cell
Volume73
Issue number5
DOIs
Publication statusPublished - 7 Mar 2019

Fingerprint

Gene Rearrangement
DNA Replication
Ubiquitination
Ovum
Xenopus
Mitosis
Chromatin
Minichromosome Maintenance Proteins
Cyclin B1
Ubiquitin-Protein Ligases
Cyclin-Dependent Kinases
Genomic Instability
Interphase
Carcinogenesis
Embryonic Structures
p97 ATPase

Keywords

  • CMG
  • DNA replication
  • fork collapse
  • genome rearrangement
  • premature mitotic entry
  • replication stress
  • template switching
  • TRAIP

Cite this

Deng, Lin ; Wu, R. Alex ; Sonneville, Remi ; Kochenova, Olga V. ; Labib, Karim ; Pellman, David ; Walter, Johannes C. / Mitotic CDK Promotes Replisome Disassembly, Fork Breakage, and Complex DNA Rearrangements. In: Molecular Cell. 2019 ; Vol. 73, No. 5. pp. 915-929.e6.
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Mitotic CDK Promotes Replisome Disassembly, Fork Breakage, and Complex DNA Rearrangements. / Deng, Lin; Wu, R. Alex; Sonneville, Remi; Kochenova, Olga V.; Labib, Karim; Pellman, David (Lead / Corresponding author); Walter, Johannes C. (Lead / Corresponding author).

In: Molecular Cell, Vol. 73, No. 5, 07.03.2019, p. 915-929.e6.

Research output: Contribution to journalArticle

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AU - Wu, R. Alex

AU - Sonneville, Remi

AU - Kochenova, Olga V.

AU - Labib, Karim

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AU - Walter, Johannes C.

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N2 - DNA replication errors generate complex chromosomal rearrangements and thereby contribute to tumorigenesis and other human diseases. One mechanism that triggers these errors is mitotic entry before the completion of DNA replication. To address how mitosis might affect DNA replication, we used Xenopus egg extracts. When mitotic CDK (Cyclin B1-CDK1) is used to drive interphase egg extracts into a mitotic state, the replicative CMG (CDC45/MCM2-7/GINS) helicase undergoes ubiquitylation on its MCM7 subunit, dependent on the E3 ubiquitin ligase TRAIP. Whether replisomes have stalled or undergone termination, CMG ubiquitylation is followed by its extraction from chromatin by the CDC48/p97 ATPase. TRAIP-dependent CMG unloading during mitosis is also seen in C. elegans early embryos. At stalled forks, CMG removal results in fork breakage and end joining events involving deletions and templated insertions. Our results identify a mitotic pathway of global replisome disassembly that can trigger replication fork collapse and DNA rearrangements. Mitotic entry before completion of DNA replication causes genome instability via an unknown mechanism. Using Xenopus egg extracts, Deng et al. find that mitotic cyclin-dependent kinase triggers replication fork breakage and DNA rearrangements. The mechanism requires TRAIP-dependent ubiquitylation of the replicative helicase followed by p97 ATPase-dependent helicase removal from chromatin.

AB - DNA replication errors generate complex chromosomal rearrangements and thereby contribute to tumorigenesis and other human diseases. One mechanism that triggers these errors is mitotic entry before the completion of DNA replication. To address how mitosis might affect DNA replication, we used Xenopus egg extracts. When mitotic CDK (Cyclin B1-CDK1) is used to drive interphase egg extracts into a mitotic state, the replicative CMG (CDC45/MCM2-7/GINS) helicase undergoes ubiquitylation on its MCM7 subunit, dependent on the E3 ubiquitin ligase TRAIP. Whether replisomes have stalled or undergone termination, CMG ubiquitylation is followed by its extraction from chromatin by the CDC48/p97 ATPase. TRAIP-dependent CMG unloading during mitosis is also seen in C. elegans early embryos. At stalled forks, CMG removal results in fork breakage and end joining events involving deletions and templated insertions. Our results identify a mitotic pathway of global replisome disassembly that can trigger replication fork collapse and DNA rearrangements. Mitotic entry before completion of DNA replication causes genome instability via an unknown mechanism. Using Xenopus egg extracts, Deng et al. find that mitotic cyclin-dependent kinase triggers replication fork breakage and DNA rearrangements. The mechanism requires TRAIP-dependent ubiquitylation of the replicative helicase followed by p97 ATPase-dependent helicase removal from chromatin.

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