SCFCyclin F-dependent degradation of CDC6 suppresses DNA re-replication

David Walter; Saskia Hoffmann; Eirini-Stavroula Komseli; Juri Rappsilber; Vassilis Gorgoulis; Claus Storgaard Sørensen

doi:10.1038/ncomms10530

SCF^{Cyclin F}-dependent degradation of CDC6 suppresses DNA re-replication

David Walter, Saskia Hoffmann, Eirini-Stavroula Komseli, Juri Rappsilber, Vassilis Gorgoulis, Claus Storgaard Sørensen

48 Citations (Scopus)

Abstract

Maintenance of genome stability requires that DNA is replicated precisely once per cell cycle. This is believed to be achieved by limiting replication origin licensing and thereby restricting the firing of each replication origin to once per cell cycle. CDC6 is essential for eukaryotic replication origin licensing, however, it is poorly understood how CDC6 activity is constrained in higher eukaryotes. Here we report that the SCF(Cyclin F) ubiquitin ligase complex prevents DNA re-replication by targeting CDC6 for proteasomal degradation late in the cell cycle. We show that CDC6 and Cyclin F interact through defined sequence motifs that promote CDC6 ubiquitylation and degradation. Absence of Cyclin F or expression of a stable mutant of CDC6 promotes re-replication and genome instability in cells lacking the CDT1 inhibitor Geminin. Together, our work reveals a novel SCF(Cyclin F)-mediated mechanism required for precise once per cell cycle replication.

Original language	English
Article number	10530
Journal	Nature Communications
Volume	7
Number of pages	10
ISSN	2041-1723
DOIs	https://doi.org/10.1038/ncomms10530
Publication status	Published - 28 Jan 2016

Keywords

Amino Acid Motifs
Cell Cycle
Cell Cycle Proteins
Cyclins
DNA Replication
Humans
Nuclear Proteins
Protein Binding
Proteolysis
SKP Cullin F-Box Protein Ligases
Journal Article
Research Support, Non-U.S. Gov't

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10.1038/ncomms10530Licence: CC BY

Cite this

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title = "SCFCyclin F-dependent degradation of CDC6 suppresses DNA re-replication",

abstract = "Maintenance of genome stability requires that DNA is replicated precisely once per cell cycle. This is believed to be achieved by limiting replication origin licensing and thereby restricting the firing of each replication origin to once per cell cycle. CDC6 is essential for eukaryotic replication origin licensing, however, it is poorly understood how CDC6 activity is constrained in higher eukaryotes. Here we report that the SCF(Cyclin F) ubiquitin ligase complex prevents DNA re-replication by targeting CDC6 for proteasomal degradation late in the cell cycle. We show that CDC6 and Cyclin F interact through defined sequence motifs that promote CDC6 ubiquitylation and degradation. Absence of Cyclin F or expression of a stable mutant of CDC6 promotes re-replication and genome instability in cells lacking the CDT1 inhibitor Geminin. Together, our work reveals a novel SCF(Cyclin F)-mediated mechanism required for precise once per cell cycle replication.",

keywords = "Amino Acid Motifs, Cell Cycle, Cell Cycle Proteins, Cyclins, DNA Replication, Humans, Nuclear Proteins, Protein Binding, Proteolysis, SKP Cullin F-Box Protein Ligases, Journal Article, Research Support, Non-U.S. Gov't",

author = "David Walter and Saskia Hoffmann and Eirini-Stavroula Komseli and Juri Rappsilber and Vassilis Gorgoulis and S{\o}rensen, {Claus Storgaard}",

year = "2016",

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doi = "10.1038/ncomms10530",

language = "English",

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journal = "Nature Communications",

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T1 - SCFCyclin F-dependent degradation of CDC6 suppresses DNA re-replication

AU - Walter, David

AU - Hoffmann, Saskia

AU - Komseli, Eirini-Stavroula

AU - Rappsilber, Juri

AU - Gorgoulis, Vassilis

AU - Sørensen, Claus Storgaard

PY - 2016/1/28

Y1 - 2016/1/28

N2 - Maintenance of genome stability requires that DNA is replicated precisely once per cell cycle. This is believed to be achieved by limiting replication origin licensing and thereby restricting the firing of each replication origin to once per cell cycle. CDC6 is essential for eukaryotic replication origin licensing, however, it is poorly understood how CDC6 activity is constrained in higher eukaryotes. Here we report that the SCF(Cyclin F) ubiquitin ligase complex prevents DNA re-replication by targeting CDC6 for proteasomal degradation late in the cell cycle. We show that CDC6 and Cyclin F interact through defined sequence motifs that promote CDC6 ubiquitylation and degradation. Absence of Cyclin F or expression of a stable mutant of CDC6 promotes re-replication and genome instability in cells lacking the CDT1 inhibitor Geminin. Together, our work reveals a novel SCF(Cyclin F)-mediated mechanism required for precise once per cell cycle replication.

AB - Maintenance of genome stability requires that DNA is replicated precisely once per cell cycle. This is believed to be achieved by limiting replication origin licensing and thereby restricting the firing of each replication origin to once per cell cycle. CDC6 is essential for eukaryotic replication origin licensing, however, it is poorly understood how CDC6 activity is constrained in higher eukaryotes. Here we report that the SCF(Cyclin F) ubiquitin ligase complex prevents DNA re-replication by targeting CDC6 for proteasomal degradation late in the cell cycle. We show that CDC6 and Cyclin F interact through defined sequence motifs that promote CDC6 ubiquitylation and degradation. Absence of Cyclin F or expression of a stable mutant of CDC6 promotes re-replication and genome instability in cells lacking the CDT1 inhibitor Geminin. Together, our work reveals a novel SCF(Cyclin F)-mediated mechanism required for precise once per cell cycle replication.

KW - Amino Acid Motifs

KW - Cell Cycle

KW - Cell Cycle Proteins

KW - Cyclins

KW - DNA Replication

KW - Humans

KW - Nuclear Proteins

KW - Protein Binding

KW - Proteolysis

KW - SKP Cullin F-Box Protein Ligases

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

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DO - 10.1038/ncomms10530

M3 - Journal article

C2 - 26818844

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 10530

ER -