Biochemistry

项目1：生物化学 RecQ家族的DNA解旋酶包括Werner综合征(WS)蛋白WRN。 WRN的突变与遗传不稳定和年龄相关疾病有关， 包括特定癌症的增加。我们的长期目标是将 WRN的生化特性和功能，并说明它们是如何对 保持基因组的完整性和避免癌症。我们的总体假设是 WRN通过促进DNA合成通过 共价损伤和解除替代次级结构。 我们有以下具体目标：[1]评估WRN在促进 通过跨损伤复制未修复的DNA损伤和替代的DNA结构(“易出错”) DNA聚合酶和DNA聚合酶8(POL8)，与项目2合作； [2]研究WRN与端粒酶和端粒DNA的相互作用。在……里面 与Project 3和北卡罗来纳大学的Jack Griffith博士合作； 确定WRN含量减少是否会导致随机突变的减少 整个基因组中缺失突变的增加；[4]来表征 显著减少的单核苷酸多态的表型表现 WRN解旋酶活性，与Core A和Gerardo Jimenez-Sanchez博士合作，在 墨西哥国家基因组医学研究所。 这些拟议的研究，连同其他项目和核心的研究，将 有助于我们理解RecQ解旋酶在人类生物学和 癌症。

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.