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.

The MRE11–RAD50–NBS1 Complex Conducts the Orchestration of Damage Signaling and Outcomes to Stress in DNA Replication and Repair

“…MRE11 can generate 3΄ overhangs to initiate HR in association with DNA2/EXO1. For example, in a recent study in a Werner syndrome–derived fibroblast cell line, the phosphorylation status of the S1133 of the WRN helicase influences the resection at breaks generated at the RF (144). Inhibition of S1133 phosphorylation in WRN results in impaired interaction with MRE11, defective MRN foci formation, and resection at the forks.…”

Osteosarcoma: Molecular Pathogenesis and iPSC Modeling

“…WRN can also unwind unusual G quadruplex (G4) DNA structures and four-way junctions [65]. WRN phosphorylation at S1133 by CDK1 favors WRN-DNA replication helicase/nuclease 2 (DNA2)-dependent long-range DNA resection and promotes homologous recombination in human fibroblasts [66]. WRN can also interact with HDAC1 and 2 to promote replication restart following replication stress in mammalian cells [67].…”

Recombine and Associate to Prevent Genomic Instability and Premature Aging

“…A recent study sheds light on the mechanisms by which the DNA resection and the switch between HR and NHEJ is regulated [Palermo et al, 2016]. With extensive immunoprecipitation and nuclear localization experiments as well as DNA fiber analysis, the authors demonstrate that phosphorylation of serine residue 1133 of the WRN protein by CDK1 controls DNA2-dependent DNA-end resection at DSBs during DNA replication.…”