SCF(Cyclin F)-dependent degradation of CDC6 suppresses DNA re-replication

Nat Commun. 2016 Jan 28;7:10530. doi: 10.1038/ncomms10530.

David Walter ¹, Saskia Hoffmann ¹, Eirini-Stavroula Komseli ², Juri Rappsilber ³ ⁴, Vassilis Gorgoulis ² ⁵, Claus Storgaard Sørensen ¹

Affiliations

1 Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, Copenhagen N 2200, Denmark.
2 Department of Histology and Embryology, School of Medicine, University of Athens, Athens GR-11527, Greece.
3 Wellcome Trust Centre for Cell Biology, University of Edinburgh, Michael Swann Building, Kings Buildings, Max Born Crescent, Edinburgh EH9 3BF, Scotland.
4 Department of Bioanalytics, Institute of Biotechnology, Technische Universität Berlin, Berlin 13355, Germany.
5 Faculty Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.

PMID: 26818844 DOI: 10.1038/ncomms10530

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.

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