C.elegans CHK-2 in meiotic chromosome organization

减数分裂染色体组织中的线虫 CHK-2

• 批准号: 7155106
• 负责人: MICHAEL S ZASTROW
• 金额: $ 4.6万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-16 至 2009-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7155106
• 关键词: Caenorhabditis elegans; DNA damage; DNA repair; DNA topoisomerases; cell cycle proteins; chemical stability; chromosome movement; gene induction /repression; genetic crossing over; genetic regulation; helminth genetics; mass spectrometry; meiosis; molecular site; nuclear membrane; nucleic acids; phosphorylation; postdoctoral investigator; protein engineering; protein kinase; protein localization; protein protein interaction; protein structure function; subcellular fractionation

DESCRIPTION (provided by applicant): My goal is to understand the mechanisms that coordinate higher order chromosome structure with formation and repair of DNA double-stranded breaks (DSBs) during meiosis, the cell division program that produces haploid gametes from diploid germ cells. Control of chromosome structure is crucial in meiosis, where DSBs are intentionally induced and repaired to form chiasmata linking chromosomes in preparation for homolog separation. The C. elegans CHK-2 protein has been identified as a key coordinator of chromosome structure, pairing, and initiation of DSB formation in meiosis. CHK-2 is an ortholog of the mammalian DNA damage checkpoint kinase Chk2, which is mutated in the familial cancer syndrome Li Fraumeni. This proposal outlines my strategy to reveal the network of control by which CHK-2 coordinates meiotic chromosome organization and DNA metabolic events to ensure genomic integrity. I will identify CHK-2 binding proteins and phosphorylation targets and determine their meiotic functions. I will test hypotheses about the mechanisms CHK-2 employs in chromosome reorganization, pairing and DSB formation. I will engineer an inactivatable CHK-2 enzyme to investigate possible CHK-2 roles after DSB formation in meiosis.

描述（由申请人提供）：我的目标是了解在减数分裂过程中协调高阶染色体结构与 DNA 双链断裂 (DSB) 形成和修复的机制，减数分裂是从二倍体生殖细胞产生单倍体配子的细胞分裂程序。染色体结构的控制在减数分裂中至关重要，其中 DSB 被有意诱导和修复，形成连接染色体的交叉，为同源分离做好准备。线虫 CHK-2 蛋白已被确定为减数分裂中染色体结构、配对和 DSB 形成启动的关键协调子。 CHK-2 是哺乳动物 DNA 损伤检查点激酶 Chk2 的直系同源物，该激酶在家族性癌症综合征 Li Fraumeni 中发生突变。该提案概述了我的策略，以揭示 CHK-2 协调减数分裂染色体组织和 DNA 代谢事件以确保基因组完整性的控制网络。我将鉴定 CHK-2 结合蛋白和磷酸化靶标并确定它们的减数分裂功能。我将测试有关 CHK-2 在染色体重组、配对和 DSB 形成中所采用机制的假设。我将设计一种不可激活的 CHK-2 酶来研究减数分裂中 DSB 形成后 CHK-2 可能的作用。