Project 1: Biochemistry The RecQ family of DNA helicases Includes the Werner syndrome (WS) protein WRN. Mutations in WRN are associated with genetic instability and age-related diseases, including an increase in specific cancers. Our long-term objective is to characterize the biochemical properties and functions of WRN, and to illuminate how they contribute to the maintenance of genomic integrity and avoidance of cancer. Our overall hypothesis is that WRN prevents collapse of replication forks by facilitating DNA synthesis past sites of covalent damage and by unwinding alternative secondary structures. We have the following Specific Aims: [1) To assess the role of WRN in facilitating replication of unrepaired DNA damage and alternate DNA structures by translesion (""""""""errorprone"""""""") DNA polymerases and by DNA polymerase 8 (Pol 8), in collaboration with Project 2;  To delineate the interactions of WRN with telomerase and telomeric DNA,. in collaboration with Project 3 and Dr. Jack Griffith at the University of North Carolina;[3) To determine if reduction in WRN content results in a decrease in random mutations throughout the genome together with an increase in deletion mutations;. [4) To characterize the phenotypic manifestations of single nucleotide polymorphisms that? greatly diminish WRN helicase activity, in collaboration with Core A and Dr. Gerardo Jimenez-Sanchez at the National Institute of Genomic Medicine, Mexico. These proposed studies, in concert with those in the other Projects and Cores, will contribute to our understanding of the roles of RecQ helicases in human biology and cancer.
The Werner syndrome protein, WRN, is required to safeguard the integrity of DNA and to avoid age-related diseases including cancer. Our proposed work on the biochemical properties and functions of WRN will further our knowledge of the mechanisms by which this disease-associated enzyme maintains the health of human cells and human populations.
|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|
|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|
|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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