Rare Diseases Symptoms Automatic Extraction

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-D2(-/-) 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 pS2056 foci suggested an increased number of DSBs processed by nonhomologous end-joining (NHEJ). Rad51 foci were also elevated in FA-D2(-/-) 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 presenting "telangiectasia" symptom

  • coats disease
  • cowden syndrome
  • cutaneous mastocytosis
  • hereditary cerebral hemorrhage with amyloidosis
  • kallmann syndrome
  • kindler syndrome
  • malignant atrophic papulosis
  • omenn syndrome
  • pendred syndrome
  • severe combined immunodeficiency
  • systemic capillary leak syndrome
  • triple a syndrome
  • waldenström macroglobulinemia
  • werner syndrome

This symptom has already been validated