Checkpoint-dependent and independent roles of the Werner syndrome protein in preserving genome integrity in response to mild replication stress.

[werner syndrome]

Werner syndrome (WS ) is a human chromosomal instability disorder associated with cancer predisposition and caused by mutations in the WRN gene . WRN helicase activity is crucial in limiting breakage at common fragile sites (CFS ), which are the preferential targets of genome instability in precancerous lesions . However , the precise function of WRN in response to mild replication stress , like that commonly used to induce breaks at CFS , is still missing . Here , we establish that WRN plays a role in mediating CHK 1 activation under moderate replication stress . We provide evidence that phosphorylation of CHK 1 relies on the ATR -mediated phosphorylation of WRN , but not on WRN helicase activity . Analysis of replication fork dynamics shows that loss of WRN checkpoint mediator function as well as of WRN helicase activity hamper replication fork progression , and lead to new origin activation to allow recovery from replication slowing upon replication stress . Furthermore , bypass of WRN checkpoint mediator function through overexpression of a phospho-mimic form of CHK 1 restores fork progression and chromosome stability to the wild-type levels . Together , these findings are the first demonstration that WRN regulates the ATR -checkpoint activation upon mild replication stress , preventing chromosome fragility .

Diseases
Validation

Diseases presenting "moderate replication stress" symptom

werner syndrome

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