Checkpoints and Double Strand Breaks in S. Pombe Meiosis

粟酒裂殖酵母减数分裂中的检查点和双链断裂

• 批准号: 8499352
• 负责人: SUSAN L FORSBURG
• 金额: $ 32.44万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8499352
• 关键词: Accounting; Address; Alkylation; Alleles; Animal Model; Biological Models; CDC7 gene; Cell Cycle; Cells; Cellular biology; Checkpoint kinase 1; Chromosome Segregation; Chromosomes; Congenital Abnormality; DNA Damage; DNA Repair; DNA biosynthesis; DNA replication fork; Data; Defect; Down Syndrome; Environmental Risk Factor; Eukaryota; Event; Fission Yeast; Funding; Genes; Genetic; Genetic Programming; Genetic Recombination; Genetic Risk; Genome; Genome Stability; Genomic Instability; Goals; Grant; Human; Investigation; Knowledge; Laboratories; Lesion; Link; Maintenance; Mediating; Meiosis; Meiotic Recombination; Molecular; Molecular Genetics; Normal Cell; Outcome; Pathway interactions; Phase; Phosphotransferases; Play; Polymerase; Process; Production; Proliferating; Proteins; Regulation; Regulator Genes; Research; Risk Factors; Role; S Phase; Signal Pathway; Spontaneous abortion; Stimulus; Stress; System; Translations; Work; Yeast Model System; Yeasts; base; checkpoint kinase 2; egg; insight; novel; prevent; programs; repaired; response; segregation; sperm cell; tool

DESCRIPTION (provided by applicant): Faithful chromosome segregation is essential to the production of viable meiotic products. While the regulation of unperturbed meiotic chromosome segregation is well understood, it is less known what happens when cells attempt meiosis in the presence of unexpected DNA damage. This proposal investigates the response to DNA damage in meiosis, using a fission yeast model system. Fission yeast is a powerful system in the analysis of damage response in the cell cycle, sharing many regulatory genes with humans. Previous studies have shown that the checkpoint system that works in proliferating cells to block the cell cycle in response to DNA damage is not functional in meiosis. Conditions that cause replication fork collapse appear to be compatible with meiotic progression. There is a genetic link between meiotic progression and the response of proliferating cells to alkylation damage that suggest translation synthesis polymerases may play a role in meiosis. These observations suggest that the meiotic response to DNA damage is substantially reprogrammed during differentiation. This is a renewal of a current project that has been funded for 1 year from ARRA (stimulus) funding. The first aim addresses the question of how the damage checkpoint kinase, Chk1, is reprogrammed in meiosis so that it does not respond to damage during S phase. The second aim asks how meiotic cells accommodate collapsing replication forks, which would be lethal during proliferation. The third aim proposes a novel role for trans-lesion synthesis (TLS) polymerases in meiosis. This is based on two observations: first, that the DDK kinase which functions during S phase also regulation meiosis and TLS, and second, that a separation of function allele in the kinase specifically disrupts meiotic divisions and TLS. The long term goal is to understand how the regulation of the damage response during meiS phase is modified to enable later meiotic events. The objective is to use fission yeast to dissect the molecular mechanisms that differ in the response to replication stress and S-phase damage in meiotic cells. The rationale is that knowledge of mechanisms that promote genome stability in meiosis will allow identification of genetic and environmental risk factors that impact human miscarriages and birth defects. The central hypothesis is that conserved activities that normally function to protect the genome are co-opted in meiosis to allow programmed genetic damage. The expected outcomes of this project are the identification and characterization of new molecular pathways. These will include potentially novel factors, likely to be conserved in higher eukaryotes. The positive impact will be a fundamental advance in understanding of the response of differentiating cells to DNA damage and genome stability, and a better understanding of risk factors during meiosis.

描述（由申请方提供）：忠实的染色体分离对于产生有活力的减数分裂产物至关重要。虽然未受干扰的减数分裂染色体分离的调节是很好理解的，但当细胞在存在意外的DNA损伤的情况下尝试减数分裂时会发生什么却不太清楚。本研究利用裂殖酵母模型系统研究减数分裂中DNA损伤的反应。裂变酵母是一个强大的系统，在分析细胞周期中的损伤反应，与人类共享许多调控基因。 先前的研究表明，在增殖细胞中工作以阻断细胞周期以响应DNA损伤的检查点系统在减数分裂中不起作用。引起复制叉崩溃的条件似乎与减数分裂进程相容。减数分裂进程和增殖细胞对烷基化损伤的反应之间存在遗传联系，这表明翻译合成聚合酶可能在减数分裂中发挥作用。这些观察结果表明，减数分裂DNA损伤的反应，基本上是在分化过程中重新编程。这是一个更新的当前项目，已资助了1年的ARRA（刺激）资金。 第一个目标是解决损伤检查点激酶Chk1如何在减数分裂中重编程，使其在S期不对损伤作出反应的问题。第二个目标是询问减数分裂细胞如何适应崩溃的复制叉，这在增殖过程中是致命的。第三个目标提出了一个新的作用，跨损伤合成（TLS）聚合酶在减数分裂。这是基于两个观察：第一，在S期发挥作用的DDK激酶也调节减数分裂和TLS，第二，激酶中功能等位基因的分离特异性地破坏减数分裂和TLS。 长期目标是了解meiS期损伤反应的调节如何被修改以使后期减数分裂事件成为可能。目的是利用裂殖酵母来剖析在减数分裂细胞中对复制应激和S期损伤的不同反应的分子机制。其基本原理是，在减数分裂中促进基因组稳定性的机制的知识将允许识别影响人类流产和出生缺陷的遗传和环境风险因素。核心假设是，通常用于保护基因组的保守活动在减数分裂中被增选，以允许程序性遗传损伤。该项目的预期成果是识别和表征新的分子途径。这些将包括可能在高等真核生物中保守的潜在新因子。积极的影响将是理解分化细胞对DNA损伤和基因组稳定性的反应以及更好地理解减数分裂期间的风险因素的根本性进展。