Journal
CELL REPORTS
Volume 18, Issue 10, Pages 2508-2520Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.02.042
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Funding
- University of Dundee [097945/Z/11/Z]
- Cancer Research UK programme [C303/A14301]
- Wellcome Trust Senior Investigator Award [WT096598MA]
- Wellcome Trust Strategic Award [097945/B/11/Z]
- Wellcome Trust [096598/Z/11/Z] Funding Source: Wellcome Trust
- Cancer Research UK [14301] Funding Source: researchfish
- Wellcome Trust [096598/Z/11/Z] Funding Source: researchfish
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Dbf4-dependent kinases (DDKs) are required for the initiation of DNA replication, their essential targets being the MCM2-7 proteins. We show that, in Xenopus laevis egg extracts and human cells, hyper-phosphorylation of DNA-bound Mcm4, but not phosphorylation of Mcm2, correlates with DNA replication. These phosphorylations are differentially affected by the DDK inhibitors PHA-767491 and XL413. We show that DDK-dependent MCM phosphorylation is reversed by protein phosphatase 1 (PP1) targeted to chromatin by Rif1. Loss of Rif1 increased MCM phosphorylation and the rate of replication initiation and also compromised the ability of cells to block initiation when challenged with replication inhibitors. We also provide evidence that Rif1 can mediate MCMdephosphorylation at replication forks and that the stability of dephosphorylated replisomes strongly depends on Chk1 activity. We propose that both replication initiation and replisome stability depend on MCM phosphorylation, which is maintained by a balance of DDK-dependent phosphorylation and Rif1-mediated dephosphorylation.
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