Perturbed replication induced genome wide or at common fragile sites is differently managed in the absence of WRN.

[werner syndrome]

The Werner syndrome protein (WRN ) is a member of the RecQ helicase family . Loss of WRN results in a human disease , the Werner syndrome (WS ), characterized by high genomic instability , elevated cancer risk and premature aging . WRN is crucial for the recovery of stalled replication forks and possesses both helicase and exonuclease enzymatic activities of uncertain biological significance . Previous work revealed that WRN promotes formation of MUS 81 -dependent double strand breaks (DSBs ) at HU-induced stalled forks , allowing replication restart at the expense of chromosome stability . Here , using cells expressing the helicase- or exonuclease-dead WRN mutant , we show that both activities of WRN are required to prevent MUS 81 -dependent breakage after HU-induced replication arrest . Moreover , we provide evidence that , in WS cells , DSBs generated by MUS 81 do not require RAD 51 activity for their formation . Surprisingly , when replication is specifically perturbed at common fragile sites (CFS ) by aphidicolin , WRN limits accumulation of ssDNA gaps and no MUS 81 -dependent DSBs are detected . However , in both cases , RAD 51 is essential to ensure viability of WS cells , although by different mechanisms . Thus , the role of WRN in response to perturbation of replication along CFS is functionally distinct from that carried out at stalled forks genome wide . Our results contribute to unveil two different mechanisms used by the cell to overcome the absence of WRN .

Diseases
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Diseases presenting "dependent double strand breaks" symptom

werner syndrome

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