) Werner syndrome (WS) is an autosomal recessive human genetic disease that is associated with genetic instability and an elevated risk of cancer. The WS gene (WRN locus) encodes a 163 kDa protein that is a member of the RecQ helicase family. In the proposed research the applicants will test two hypotheses: 1) that the loss of WRN helicase activity causes genetic instability in WS; and 2) that WRN may limit genetic instability in vivo by insuring the accurate repair of DNA double-strand breaks (DSBs). Results of the proposed research will establish a causal link between the loss of WRN helicase function and genetic instability in WS cells. This project, in conjunction with other projects and Core A, aims to identify where the WRN protein functions in cellular nucleic acid metabolism, and how loss of function promotes genetic instability in human somatic cells. The investigators will also provide new information on DNA double-strand break repair in human somatic cells.
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| Schmitt, Michael W; Pritchard, Justin R; Leighow, Scott M et al. (2018) Single-Molecule Sequencing Reveals Patterns of Preexisting Drug Resistance That Suggest Treatment Strategies in Philadelphia-Positive Leukemias. Clin Cancer Res 24:5321-5334 |
| Mikheev, Andrei M; Mikheeva, Svetlana A; Severs, Liza J et al. (2018) Targeting TWIST1 through loss of function inhibits tumorigenicity of human glioblastoma. Mol Oncol 12:1188-1202 |
| Kamath-Loeb, Ashwini S; Zavala-van Rankin, Diego G; Flores-Morales, Jeny et al. (2017) Homozygosity for the WRN Helicase-Inactivating Variant, R834C, does not confer a Werner syndrome clinical phenotype. Sci Rep 7:44081 |
| Oshima, Junko; Sidorova, Julia M; Monnat Jr, Raymond J (2017) Werner syndrome: Clinical features, pathogenesis and potential therapeutic interventions. Ageing Res Rev 33:105-114 |
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