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

基本信息

批准号：
8269785
负责人：
SUSAN L FORSBURG
金额：
$ 33.62万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
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/8269785
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

项目摘要

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（由申请人提供）：忠实的染色体分离对于生产可行的减数分裂产物至关重要。虽然不受干扰的减数分裂染色体分离的调节已被充分了解，但当细胞在出现意外 DNA 损伤的情况下尝试减数分裂时会发生什么，人们却知之甚少。该提案使用裂殖酵母模型系统研究减数分裂中 DNA 损伤的反应。裂殖酵母是分析细胞周期损伤反应的强大系统，与人类共享许多调控基因。先前的研究表明，在增殖细胞中发挥作用以阻断细胞周期以应对 DNA 损伤的检查点系统在减数分裂中不起作用。导致复制叉崩溃的条件似乎与减数分裂进展相容。减数分裂进程与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。这些观察表明，减数分裂对 DNA 损伤的反应在分化过程中显着重新编程。这是当前项目的更新，该项目已由 ARRA（刺激）资金资助一年。第一个目标解决损伤检查点激酶 Chk1 如何在减数分裂中重新编程，使其不对 S 期损伤做出反应的问题。第二个目标是询问减数分裂细胞如何适应折叠的复制叉，这在增殖过程中是致命的。第三个目标提出跨损伤合成（TLS）聚合酶在减数分裂中的新作用。这是基于两个观察结果：首先，在 S 期发挥作用的 DDK 激酶也调节减数分裂和 TLS，其次，激酶中功能等位基因的分离特异性地破坏减数分裂和 TLS。长期目标是了解如何修改 meiS 阶段损伤反应的调节以实现后来的减数分裂事件。目的是利用裂殖酵母剖析减数分裂细胞对复制应激和 S 期损伤的不同反应的分子机制。其基本原理是，了解促进减数分裂中基因组稳定性的机制将有助于识别影响人类流产和出生缺陷的遗传和环境风险因素。中心假设是，通常起到保护基因组作用的保守活性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新分子途径的识别和表征。这些将包括可能在高等真核生物中保守的潜在新颖因素。其积极影响将是在了解分化细胞对 DNA 损伤和基因组稳定性的反应方面取得根本性进展，并更好地了解减数分裂期间的风险因素。