The long term goal of this project is to provide a detailed molecular description of in vivo functions of the Werner syndrome protein (WRN, also known as RECQ3 or RECQL2) in human somatic cells.
Specific Aims focus on answering three questions: 1. defining the WRN functional pathway in human somatic cells; 2. identifying in vivo substrates for WRN function in human somatic cells; and 3. determining DNA damage response pathway activation and responsiveness in cells lacking WRN function. This work will test four hypotheses: 1) that WRN acts in somatic cells to resolve aberrant DNA structures or promote the repair of DNA damage that can block, stall or disrupt DNA replication during S-phase; 2) that WRN may play a direct role in the repair of stalled or regressed replication forks; 3) that these resolution/repair functions depend on both catalytic activities of the WRN protein; and 4) that DNA damage response pathways are constitutively activated in human somatic cells that lack WRN, leading to decrements in cell cycle progression, viability and genomic stability. The identification of physiologic roles for the WRN protein in nucleic acid metabolism will provide a detailed understanding of how WRN acts to insure genomic stability, and a model to determine how loss of WRN function promotes the genetic instability, mutagenesis and cellular growth deficits that are central to Werner syndrome pathogenesis.
|Orozco, Javier I J; Knijnenburg, Theo A; Manughian-Peter, Ayla O et al. (2018) Epigenetic profiling for the molecular classification of metastatic brain tumors. Nat Commun 9:4627|
|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|
|Lee, Su-In; Celik, Safiye; Logsdon, Benjamin A et al. (2018) A machine learning approach to integrate big data for precision medicine in acute myeloid leukemia. Nat Commun 9:42|
|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|
|Davis, Luther; Zhang, Yinbo; Maizels, Nancy (2018) Assaying Repair at DNA Nicks. Methods Enzymol 601:71-89|
|Yu, Ming; Heinzerling, Tai J; Grady, William M (2018) DNA Methylation Analysis Using Droplet Digital PCR. Methods Mol Biol 1768:363-383|
|Knijnenburg, Theo A; Wang, Linghua; Zimmermann, Michael T et al. (2018) Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas. Cell Rep 23:239-254.e6|
|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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