CDK1 phosphorylates WRN at collapsed replication forks

Valentina Palermo, Sara Rinalducci, Massimo Sanchez, Francesca Grillini, Joshua A. Sommers, Robert M. Brosh, Lello Zolla, Annapaola Franchitto and Pietro Pichierri ()
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Valentina Palermo: Section of Experimental and Computational Carcinogenesis, Istituto Superiore di Sanità
Sara Rinalducci: Proteomics Lab, Università della Tuscia
Massimo Sanchez: Section of Gene and Cell Therapy, Istituto Superiore di Sanità
Francesca Grillini: Section of Experimental and Computational Carcinogenesis, Istituto Superiore di Sanità
Joshua A. Sommers: Laboratory of Molecular Gerontology, National Institute on Aging, NIH, NIH Biomedical Research Center
Robert M. Brosh: Laboratory of Molecular Gerontology, National Institute on Aging, NIH, NIH Biomedical Research Center
Lello Zolla: Proteomics Lab, Università della Tuscia
Annapaola Franchitto: Section of Molecular Epidemiology, Istituto Superiore di Sanità
Pietro Pichierri: Section of Experimental and Computational Carcinogenesis, Istituto Superiore di Sanità

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12880

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