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Nat Commun. 2016 Sep 16;7:12880. doi: 10.1038/ncomms12880.

CDK1 phosphorylates WRN at collapsed replication forks.

Author information

1
Section of Experimental and Computational Carcinogenesis, Department of Environment and Health, Istituto Superiore di Sanità, Rome 00161, Italy.
2
Proteomics Lab, Department of Ecology and Biology, Università della Tuscia, 01100 Viterbo, Italy.
3
Section of Gene and Cell Therapy, Department of Neurosciences, Istituto Superiore di Sanità, 00161 Rome, Italy.
4
Laboratory of Molecular Gerontology, National Institute on Aging, NIH, NIH Biomedical Research Center, Baltimore, Maryland 21224, USA.
5
Section of Molecular Epidemiology, Department of Environment and Health, Istituto Superiore di Sanità, 00161 Rome, Italy.

Abstract

Regulation of end-processing is critical for accurate repair and to switch between homologous recombination (HR) and non-homologous end joining (NHEJ). End resection is a two-stage process but very little is known about regulation of the long-range resection, especially in humans. WRN participates in one of the two alternative long-range resection pathways mediated by DNA2 or EXO1. Here we demonstrate that phosphorylation of WRN by CDK1 is essential to perform DNA2-dependent end resection at replication-related DSBs, promoting HR, replication recovery and chromosome stability. Mechanistically, S1133 phosphorylation of WRN is dispensable for relocalization in foci but is involved in the interaction with the MRE11 complex. Loss of WRN phosphorylation negatively affects MRE11 foci formation and acts in a dominant negative manner to prevent long-range resection altogether, thereby licensing NHEJ at collapsed forks. Collectively, we unveil a CDK1-dependent regulation of the WRN-DNA2-mediated resection and identify an undescribed function of WRN as a DSB repair pathway switch.

PMID:
27634057
PMCID:
PMC5028418
DOI:
10.1038/ncomms12880
[Indexed for MEDLINE]
Free PMC Article

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