Werner syndrome helicase has a critical role in DNA damage responses in the absence of a functional fanconi anemia pathway.

[werner syndrome]

Werner syndrome is genetically linked to mutations in WRN that encodes a DNA helicase-nuclease believed to operate at stalled replication forks . Using a newly identified small -molecule inhibitor of WRN helicase (NSC 617145 ), we investigated the role of WRN in the interstrand cross-link (ICL ) response in cells derived from patients with Fanconi anemia , a hereditary disorder characterized by bone marrow failure and cancer . In FA -D 2 (-/-) cells , NSC 617145 acted synergistically with very low concentrations of mitomycin C to inhibit proliferation in a WRN -dependent manner and induce double -strand breaks (DSB ) and chromosomal abnormalities . Under these conditions , ataxia-telangiectasia mutated activation and accumulation of DNA-dependent protein kinase , catalytic subunit pS 2056 foci suggested an increased number of DSBs processed by nonhomologous end-joining (NHEJ ). Rad 51 foci were also elevated in FA -D 2 (-/-) cells exposed to NSC 617145 and mitomycin C , suggesting that WRN helicase inhibition interferes with later steps of homologous recombination at ICL-induced DSBs . Thus , when the Fanconi anemia pathway is defective , WRN helicase inhibition perturbs the normal ICL response , leading to NHEJ activation . Potential implication for treatment of Fanconi anemia -deficient tumors by their sensitization to DNA cross-linking agents is discussed .

Diseases
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Diseases presenting "nhej activation" symptom

werner syndrome

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