Biochemistry

项目1：生物化学 RecQ DNA解旋酶家族包括Werner综合征（WS）蛋白WRN。 WRN的突变与遗传不稳定性和年龄相关疾病有关， 包括特定癌症的增加。我们的长期目标是描述 WRN的生化特性和功能，并阐明它们如何有助于 维持基因组完整性和避免癌症。我们的总体假设是 WRN通过促进DNA合成，防止复制叉的崩溃。 共价损伤和解旋替代的二级结构。 我们有以下具体目标：[1]评估WRN在促进 未修复的DNA损伤的复制和通过跨损伤的交替DNA结构（“易错”） DNA聚合酶和DNA聚合酶8（Pol 8），与项目2合作; [2]研究WRN与端粒酶和端粒DNA的相互作用。在 与项目3和北卡罗来纳州大学的Jack Griffith博士合作; [3] 确定WRN含量的减少是否导致随机突变的减少 在整个基因组中，缺失突变增加;。[4)表征 单核苷酸多态性的表型表现， WRN解旋酶活性，与Core A和Gerardo Jimenez-Sanchez博士合作， 墨西哥国家基因组医学研究所 这些拟议研究与其他项目和核心研究的研究将 有助于我们理解RecQ解旋酶在人类生物学中的作用， 癌

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; [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.