DNA Helicases in Recombination and Repair

DNA 解旋酶在重组和修复中的作用

• 批准号: 7595770
• 负责人: Hannah L. Klein
• 金额: $ 28.25万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7595770
• 关键词: Biological; Bypass; Cell Cycle Checkpoint; Cells; Controlled Study; DNA; DNA Binding; DNA Damage; DNA Repair; DNA Sequence Rearrangement; DNA biosynthesis; DNA damage checkpoint; Defect; Equilibrium; Excision; Filament; Gene Rearrangement; Genes; Genetic; Genetic Recombination; Genome Stability; Genomics; Goals; Growth; Human; Lesion; Loss of Heterozygosity; Maintenance; Malignant Neoplasms; Mediating; Mediator of activation protein; Microscopic; Mitotic; Mitotic Cell Cycle; Modeling; Mutation; Pathway interactions; Phase; Process; Proteins; Regulation; Role; Silent Mutation; Sister Chromatid; Testing; attenuation; chromosome mutation; cohesion; ds-DNA; helicase; homologous recombination; mutant; overexpression; recombinational repair; repaired; research study; response

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to understand the biological roles of DNA helicase and helicase-related genes in recognizing and repairing spontaneous damage that occurs during the mitotic cell cycle. Mitotic DNA damage is dangerous to DNA replication, and can result in stalled or collapsed replication forks. The DNA damage is processed by lesion bypass pathways or homologous recombination, depending on the type of DNA damage. Homologous recombination (HR) must be tightly regulated to avoid genomic rearrangements. Defects in recombination, particularly from helicase and helicase-like genes, can result in blocked intermediates that trigger a cell cycle checkpoint. We will investigate the roles of helicase and helicase-like genes in repair and recombination, studying the control over with which pathway is used to repair damage during replication. The Srs2 DNA helicase and the SWI/SNF-like proteins Rad54, Rdh54 and Tid4 act against Rad51, an essential factor in homologous recombination. The Srs2 DNA helicase can regulate the type of repair pathway by disrupting a Rad51 filament, one of the first intermediates in HR. We will investigate how the balance between HR and postreplication repair (PRR) is achieved through the balance between the Srs2 helicase and Rad51 protein, and whether replication components have a role in this balance. Rad54, Rdh54 and Tid4 remove Rad51 from double stranded DNA results in a cell cycle checkpoint arrest and increased DNA rearrangements. The specific aims are to understand why the nonessential Srs2 DNA helicase becomes essential in sister chromatid cohesion defective strains and why excess Rad51 protein is lethal, and the roles of the SWI/SNF-like proteins Rdh54 and Tid4 in maintenance of genomic stability. These goals will be achieved by genetic studies, examination of the consequences of Rad51 overexpression, microscopic examination of cells for markers of DNA damage, studies on the role of sister chromatid cohesion recombination repair. DNA repair mechanisms are essential for mutation avoidance and stability of the genetic information. When the repair mechanisms are defective, mutations and chromosome changes occur. These reveal normally silent mutations, which now drive cells to uncontrolled growth associated with human cancers.

描述（由申请人提供）：该提案的长期目标是了解DNA解旋酶和解旋酶相关基因在识别和修复有丝分裂细胞周期中发生的自发损伤中的生物学作用。有丝分裂DNA损伤对DNA复制有危险，并且可能导致停滞或折叠的复制叉。 DNA损伤是通过病变旁路途径或同源重组处理的，具体取决于DNA损伤的类型。必须严格调节同源重组（HR），以避免基因组重排。重组中的缺陷，特别是从解旋酶和解旋酶样基因中的缺陷，可能导致触发细胞周期检查点的中间体阻塞。我们将研究解旋酶和解旋酶样基因在修复和重组中的作用，研究在复制过程中使用途径来修复途径的控制。 SRS2 DNA解旋酶和SWI/SNF样蛋白RAD54，RDH54和TID4对RAD51作用，这是同源重组的重要因素。 SRS2 DNA解旋酶可以通过破坏RAD51细丝（HR中的第一批中间体之一）来调节修复途径的类型。我们将通过SRS2解旋酶和RAD51蛋白之间的平衡以及复制成分在这种平衡中的作用来实现人力资源和后置修复（PRR）之间的平衡（PRR）之间的平衡。 RAD54，RDH54和TID4从双链DNA中删除Rad51导致细胞周期检查点停滞并增加DNA重排。具体的目的是了解为什么非必需的SRS2 DNA解旋酶在姐妹染色单体内聚菌株中至关重要，以及为什么多余的RAD51蛋白具有致死性以及SWI/SNF样蛋白RDH54和TID4在维持基因组稳定性中的作用。这些目标将通过遗传研究来实现，检查RAD51过表达的后果，对DNA损伤标记的细胞的显微镜检查，姐妹染色单体凝聚重组修复的作用研究。 DNA修复机制对于避免突变和遗传信息的稳定性至关重要。当修复机制有缺陷时，突变和染色体变化发生。这些揭示了通常的无声突变，现在将细胞驱动到与人类癌症相关的不受控制的生长。