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

TY - JOUR

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

U2 - 10.1038/ncomms10530

DO - 10.1038/ncomms10530

M3 - Journal article

C2 - 26818844

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 10530

ER -