The long term goal of research proposed in this Program Project is to provide a detailed description of the Werner syndrome protein (WRN) functional pathway in human somatic cells, and to determine how a loss of WRN function leads to the cellular and clinical phenotypes of Werner syndrome that include constitutional genetic instability and an elevated risk of cancer. The Werner Syndrome Program Project is an integrated research effort consisting of 4 Projects and 2 Cores that are collectively focused on the following questions: 1. what proteins and DNA substrates constitute the WRN functional pathway in human somatic cells? 2. what are the important physiologic functions of WRN in human somatic cells? 3. how does loss of WRN function lead to genetic instability, selective DNA damage hypersensitivity and cell proliferation defects? 4. what role do WRN polymorphisms and mutations play in promoting the risk or pathogenesis of cancer or other diseases in the general population? Results of the proposed research will delineate normal functions of the WRN protein in human somatic cells, and how the loss of function leads to pathogenesis of the Werner syndrome cellular and clinical phenotypes. Results of the proposed research will also indicate the potential importance of common heritable alterations in WRN expression---polymorphisms in, or loss of one active copy of, the WRN gene--in promoting cancer risk and pathogenesis in the general population.
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| Salk, Jesse J; Schmitt, Michael W; Loeb, Lawrence A (2018) Enhancing the accuracy of next-generation sequencing for detecting rare and subclonal mutations. Nat Rev Genet 19:269-285 |
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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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