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.
Highlights
Regulation of end-processing is critical for accurate repair and to switch between homologous recombination (HR) and non-homologous end joining (NHEJ)
It is well established that cyclin-dependent kinases (CDKs) regulate the initial steps of the end-resection process, less is known about the regulation of long-range end resection[8,13], especially in human cells
We describe a novel regulatory mechanism controlling long-range resection at replicationdependent double-strand breaks (DSBs) and repair pathway choice through the phosphorylation of WRN mediated by CDK1
Summary
Regulation of end-processing is critical for accurate repair and to switch between homologous recombination (HR) and non-homologous end joining (NHEJ). 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. 14); whether they regulate the DNA2-dependent longrange resection pathway is unknown It is still debated whether DNA2 acts preferentially with WRN or BLM during long-range resection[15,16,17]. WRN may play a prominent role to regulate end resection at replication-dependent DSBs. Here we describe CDK1-mediated phosphorylation of WRN, which represents a novel mechanism by which CDK1 controls long-range end resection and DNA repair pathway choice at replication-dependent DSBs in human cells. Abrogation of WRN phosphorylation impinges on proper MRE11 recruitment, stimulating NHEJ repair of replication-dependent DSBs and enhancing genome instability
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