GENOME STABILITY THROUGH BLOOM SYNDROME HELICASE AND RAD51 COMPLEX FORMATION

通过 Bloom 综合征解旋酶和 RAD51 复合物形成实现基因组稳定性

• 批准号: 7609967
• 负责人: Karen H. Almeida
• 金额: $ 8.07万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7609967
• 关键词: Address; Amino Acid Sequence; Amino Acids; BLM gene; Bloom Syndrome; Bloom syndrome protein; Cells; Class; Classification; Complex; Computer Retrieval of Information on Scientific Projects Database; DNA; Disease; Event; Exhibits; Funding; Genome; Genome Stability; Genomic Instability; Goals; Grant; In Vitro; Institution; Knowledge; Mediating; Molecular; Mutagens; Mutation; Pathway interactions; Play; Proteins; Research; Research Personnel; Resources; Role; Sister Chromatid Exchange; Source; United States National Institutes of Health; helicase; neoplastic cell; recombinational repair; research study; response; restoration

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The hallmark feature of tumor cells is a highly unstable genome. Bloom syndrome (BS), an autosomal recessive disorder that results from mutation of the BLM gene, exhibits extraordinarily high levels of sister chromatid exchange (SCE) events, a marker of genomic instability. BLM protein may influence genome stability through 3-5 DNA helicase activity that can stabilize stalled replication forks caused by damage to the DNA. Since many classes of genotoxic agents have been shown to block replication, this information is essential to the understanding of the cellular responses to genotoxic agents. The homologous recombinational repair (HRR) pathway is required for SCE formation and restoration of a collapsed replication fork. Therefore, HRR is essential in maintaining genomic stability. Rad51, a protein central to the HRR pathway, physically interacts with BLM and thus could play a role in the elevated levels of SCE events seen in BS cells. The goal of this proposal is to define the amino acid residues of BLM physically interacting with Rad51 and to determine the complexs function as a molecular switch through which the cell can govern pathway choice. Knowledge of the physical parameters will assist in the determination of the functional significance of complex formation. The experiments proposed will address the following Specific Aims: (1.) Refine the BLM amino acid sequence responsible for mediating complex formation with Rad51 through systematic deletion of 25 amino acid increments from the termini; (2.) Establish that the SCE marker of genomic instability is dependent on complex formation between BLM and Rad51; (3.) Demonstrate that the BLM-Rad51 complex functions as a molecular switch by modulating the in vitro activity of each protein. We will evaluate BLM helicase activity as a function of Rad51 partnership and strand displacement activity of Rad51 as a function of BLM partnership.

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