Functional elucidation of BRCA1-containing complexes

含 BRCA1 复合物的功能阐明

• 批准号: 7477333
• 负责人: RAMIN SHIEKHATTAR
• 金额: $ 20.14万
• 依托单位: CENTER FOR GENOMIC REGULATION
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7477333
• 关键词: BARD1 gene; BRCA1 Associated RING Domain 1 Protein; BRCA1 gene; BRCA2 gene; Biochemical; Biological Process; Breast; Cancerous; Cell Cycle; Cell Cycle Stage; Cells; Chromatin; Chromatin Remodeling Factor; Chromatin Structure; Chromosome Fragile Sites; Complex; DNA; DNA Repair; DNA Replication Induction; DNA biosynthesis; DNA chemical synthesis; DNA strand break; Data; Development; Disease; Event; Fanconi' s Anemia; Foundations; Germ-Line Mutation; Heterochromatin; Human; In Vitro; Individual; Laboratories; Lesion; Malignant Neoplasms; Malignant neoplasm of ovary; Maps; Mediating; Methods; Molecular; Monitor; Multiprotein Complexes; Mutation; Neoplasms; Nuclear; Pattern; Phase; Phosphorylation Site; Play; Premalignant; Protein Dephosphorylation; Proteins; Regulation; Reporting; Research Personnel; Role; Role playing therapy; Signal Transduction; Site; Small Interfering RNA; Staining method; Stains; Stress; Structure; Testing; Time; Transcriptional Regulation; United States; Woman; Work; X Inactivation; biological adaptation to stress; design; helicase; in vivo; insight; malignant breast neoplasm; mutant; novel; polypeptide; programs; repaired; research study; response; tumorigenesis; ubiquitin ligase; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Our laboratory is focused on the function of nuclear multiprotein complexes containing BRCA1. We have used biochemical methods to isolate and functionally characterize two distinct BRCA1-containing complexes termed BRCC and BRCA1-BACH1. Although both complexes share a common core subunits (BRCA1, BARD1, BRCA2), each contain unique subunits that distinguish them apart. While BRCC contains two novel subunits BRCC45 and a signalosome-like subunit, BRCC36, the second complex contains the DNA helicase, BACH1. Although BRCA1 has been shown to display a distinct nuclear pattern during the S phase of the cell, the dynamic changes in the polypeptide composition and biochemical function of BRCA1-containing complexes during the cell cycle have not been thoroughly studied. This proposal is aimed at gaining insight into the biological function of these two complexes in vitro and in vivo. We hypothesize that the two BRCA1-containing complexes play roles in the DNA replication stress response. The three Aims are designed to provide a thorough physical and functional characterization of BRCA1-containing complexes. Aim 1 will assess the physical and functional association of BACH1, BRCC36 and BRCC45 with BRCA1 at different stages of the cell cycle and following DNA replication stress response. Aim 2 describes a detailed functional analysis of the two complexes, BRCC and BACH1-BRCA1 in responsiveness to replication stress and in regulation of common fragile site stability. Aim 3 extends the work to analysis of the effect of BRCC and BACH1-BRCA1 complexes on regulation of late replicating DNA and heterochromatin structure.

描述（由申请人提供）：我们的实验室专注于含有BRCA 1的核多蛋白复合物的功能。我们已经使用生物化学方法分离和功能特性的两个不同的BRCA 1含有复合物称为BRCC和BRCA 1-BACH 1。虽然这两种复合物都有一个共同的核心亚基（BRCA 1，BARD 1，BRCA 2），但每个复合物都含有独特的亚基，将它们区分开来。BRCC含有两个新的亚基BRCC 45和一个信号体样亚基BRCC 36，第二个复合体含有DNA解旋酶BACH 1。虽然BRCA 1已被证明在细胞的S期期间显示出独特的核模式，但在细胞周期期间，含有BRCA 1的复合物的多肽组成和生化功能的动态变化尚未被彻底研究。该建议旨在深入了解这两种复合物在体外和体内的生物学功能。我们推测这两个含BRCA 1的复合物在DNA复制应激反应中发挥作用。这三个目标旨在提供含BRCA 1复合物的全面物理和功能表征。目的1将评估BACH 1，BRCC 36和BRCC 45与BRCA 1在细胞周期的不同阶段和DNA复制应激反应后的物理和功能关联。目的2描述了详细的功能分析的两个复合物，BRCC和BACH 1-BRCA 1的复制应激反应和调节常见的脆性位点的稳定性。目的3：分析BRCC和BACH 1-BRCA 1复合物对晚期复制DNA和异染色质结构的调控作用。