) Defective function of the DNA helicase WRN in Werner syndrome (WS) is characterized by prolongation of S phase, chromosome translocations and an increased incidence of malignancies of unusual types. WS cells are sensitive to a restricted set of clastogens and mutagens and this sensitivity is very different from other known helicase-deficiency disorders. This suggests a different DNA substrate and/or a novel function for WRN. The model of the investigators proposes that WRN is required for the efficient and accurate repair or toleration in S phase of a specific set of blocking lesions and that failure to do so leads to aberrations in DNA replication. They believe that this defect is reflected in hypersensitivity of WRN-/- cells to a particular subset of DNA damaging agents that include 4NQO. Their model also proposes that the elevated incidence of certain uncommon tumors in WS reflects intrinsic differences in their progenitor cells to susceptibility to these DNA lesions or the capacity to repair them. Specifically, the applicants will test the following hypotheses: 1. The function of WRN is required for normal S phase progression. 2. The hypersensitivity of WS cells to the drug 4NQO is due to damage that is sustained in or carried into S phase. 3. That WRN is required to prevent blockage of S phase by specific blocking DNA adducts. 4. The unusual tissue distribution of cancer in Werner syndrome patients is related to differences in genotoxin sensitivity and genetic instability between specific cell lineages.
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