Mechanisms of meiotic and mitotic recombination

减数分裂和有丝分裂重组机制

• 批准号: 9282741
• 负责人: JEFF J. SEKELSKY
• 金额: $ 52.01万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9282741
• 关键词: Address; Aneuploidy; Biochemical; Biological Assay; Biological Models; Cell division; Cells; Chromosome abnormality; Chromosomes; Cleaved cell; Congenital Abnormality; DNA Damage; DNA Double Strand Break; Dangerousness; Drosophila genus; Ensure; Genetic; Genetic Recombination; Genomic Instability; Holliday Junction Resolvases; Human; In Vitro; Laboratories; Lead; Malignant Neoplasms; Meiosis; Meiotic Recombination; Mitotic; Mitotic Recombination; Outcome; Pregnancy loss; Process; Proliferating; Research; Spontaneous abortion; Sterility; Tissues; Trisomy; deep sequencing; egg; helicase; public health relevance; repaired; segregation; sperm cell; tumorigenesis

 DESCRIPTION (provided by applicant): Recombination is both a means to avoid genome instability and to a process that generates genome instability. In meiosis, DNA double-strand breaks are repaired into crossovers that are essential for accurate segregation of homologous chromosomes; defects in this process result in sterility or aneuploidy, the major cause of pregnancy loss and trisomy. Conversely, in mitotically proliferating cells double-strand breaks are a dangerous class of DNA damage. Repair of breaks in this context is done without making crossovers; formation of crossovers in mitotic cells can lead to chromosome rearrangements and tumorigenesis. Research in my laboratory focuses on mechanisms that promote crossovers in meiotic cells and non-crossover outcomes of repair in mitotic cells. We focus on helicases that disassemble recombination intermediates to generate non-crossovers and Holliday junction resolvases that cleave intermediates and can generate crossovers. Our central approach is to take advantage of unique features of Drosophila to address important questions that are difficult to answer with other model systems. In addition, we have developed repair assays to use in human cells, done in vitro biochemical studies, and begun deep sequencing projects. This combination of approaches will help to continue to drive the recombination field forward.

 描述（适用提供）：重组既是避免基因组不稳定性的手段，又是产生基因组不稳定性的过程。在减数分裂中，DNA双链断裂被修复到交叉中，这对于准确分离同源染色体至关重要。此过程中的缺陷导致不育或非整倍性，这是妊娠丧失和三体造成的主要原因。相反，在有丝分裂的增殖细胞中，双链断裂是一类危险的DNA损伤。在这种情况下，修复休息时间是在不进行跨界的情况下完成的；有丝分裂细胞中跨界的形成会导致染色体重排和肿瘤发生。我的实验室的研究重点是促进减数分裂细胞和有丝分裂细胞修复的非交叉结局的机制。我们专注于拆卸重组中间体的解旋酶，以产生非交叉和霍利迪连接分辨率，从而清除中间体并可以产生交叉。我们的中心方法是利用果蝇的独特特征来解决其他模型系统难以回答的重要问题。此外，我们开发了用于在人类细胞中使用的修复刺客，进行体外生化研究并开始深入测序项目。这种方法的组合将有助于继续推动重组领域的前进。