title: CDK1 phosphorylates WRN at collapsed replication forks.
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.
authors.affiliation: Section of Experimental and Computational Carcinogenesis, Department of Environment and Health, Istituto Superiore di Sanità, Rome 00161, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Palermo
authors.affiliation: Proteomics Lab, Department of Ecology and Biology, Università della Tuscia, 01100 Viterbo, Italy.
authors.forename: Sara
authors.identifier: 0000-0002-2703-6105
authors.initials: S
authors.lastname: Rinalducci
authors.affiliation: Section of Gene and Cell Therapy, Department of Neurosciences, Istituto Superiore di Sanità, 00161 Rome, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Sanchez
authors.affiliation: Section of Experimental and Computational Carcinogenesis, Department of Environment and Health, Istituto Superiore di Sanità, Rome 00161, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Grillini
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, NIH, NIH Biomedical Research Center, Baltimore, Maryland 21224, USA.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Sommers
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, NIH, NIH Biomedical Research Center, Baltimore, Maryland 21224, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Brosh
authors.affiliation: Proteomics Lab, Department of Ecology and Biology, Università della Tuscia, 01100 Viterbo, Italy.
authors.forename: Lello
authors.initials: L
authors.lastname: Zolla
authors.affiliation: Section of Molecular Epidemiology, Department of Environment and Health, Istituto Superiore di Sanità, 00161 Rome, Italy.
authors.forename: Annapaola
authors.initials: A
authors.lastname: Franchitto
authors.affiliation: Section of Experimental and Computational Carcinogenesis, Department of Environment and Health, Istituto Superiore di Sanità, Rome 00161, Italy.
authors.forename: Pietro
authors.identifier: 0000-0002-2702-3523
authors.initials: P
authors.lastname: Pichierri
mesh_terms: D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000502:physiology; D004261:DNA Replication; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D042822:Genomic Instability; D059765:Homologous Recombination; D006801:Humans; D010766:Phosphorylation; D000071657:Werner Syndrome Helicase / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase