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: 7846742
• 负责人: SUSAN L FORSBURG
• 金额: $ 32.42万
• 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 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7846742
• 关键词: Age; Alleles; Animal Model; Behavior; CDC7 gene; Cell Cycle Arrest; Cell Division Process; Cells; Cellular biology; Checkpoint kinase 1; Chromosome Segregation; Chromosome abnormality; Chromosomes; Collection; Complex; Congenital Abnormality; Coupling; DNA; DNA Damage; DNA biosynthesis; DNA damage checkpoint; Data; Defect; Diploidy; Down-Regulation; Elements; Ensure; Eukaryota; Event; Fission Yeast; Generations; Genetic; Genetic Recombination; Genome; Genome Stability; Germ Cells; Growth; Haploidy; Health; Human; Link; Mediating; Meiosis; Methods; Mitotic; Modeling; Molecular Genetics; Monitor; Organism; Pathway interactions; Phase; Phosphotransferases; Proteins; Recombinants; Regulation; Replication Initiation; Reproduction; Role; Spontaneous abortion; Staging; Technology; Time; genome wide association study; genome-wide analysis; inhibitor/antagonist; insight; mutant; offspring; prevent; programs; response; tool; zygote

Meiosis is a specialized cell division process, common to sexually reproducing eukaryotes, that reduces diploid zygotes to recombinant haploid gametes. Defects in meiosis have profound consequences for human health. More than half of human miscarriages result from gross chromosomal abnormalities, most of which result from errors during meiosis. Thus, understanding chromosomal events during meiosis is fundamental to understanding human reproduction. A crucial component of meiosis is the generation of programmed breaks to initiate recombination and the exchange of genetic information. In contrast to mitotic growth, meiotic cells deliberately create damage to their genome, which must be timed appropriately to facilitate crossovers. This project investigates how the cell changes its checkpoint responses from protecting the genome and preventing random double strand breaks, to actively damaging the genome in a regulated program during early stages of meiosis. The broad hypothesis is that the kinases that regulate normal progression through S phase are coopted in meiosis to allow recombinogenic breaks to occur. The choice of model organism is key. Fission yeast has a simple meiosis, which can be induced from haploids as well as normal diploids. This makes S. pombe particularly useful in the elucidation of basic principles that initiate recombination, without the complications of more complex organisms. Moreover, fission yeast is well established as a model for chromosome behavior, and has a complete collection of tools and technology. The first aim asks how the cell modifies its normal damage response during meiosis, because the Chk1 checkpoint kinase pathway is not activated during meiosis. This aim will use genetic, molecular, and cell biology methods to examine how the Chk1 pathway is interrupted and identify any new factors responsible. The second aim asks how the replication kinase Hsk1 (Cdc7) functions in meiosis to promote double strand breaks and proper chromosome segregation. This study will provide important insights into mechanisms of genome stability during meiotic differentiation.

减数分裂是一种专门的细胞分裂过程，是性繁殖真核生物常见的，可将二倍体Zygotes降低为重组单倍体配子。减数分裂缺陷对人类健康产生了深远的影响。超过一半的人类流产是由总染色体异常引起的，其中大部分是由于减数分裂过程中的错误。因此，了解减数分裂过程中的染色体事件对于理解人类繁殖至关重要。减数分裂的一个关键组成部分是启动重组和遗传信息交换的程序中断的产生。与有丝分裂生长相反，减数分裂细胞故意对其基因组造成损害，必须适当定时以促进跨界。该项目研究了细胞如何改变其检查点的响应，免受保护基因组和防止随机双链断裂的影响，从而在减数分裂的早期阶段积极损害受管制程序中的基因组。广泛的假设是，在减数分裂中掌握了调节正常进展的激酶，以允许发生重组性断裂。模型生物的选择是关键。裂变酵母具有简单的减数分裂，可以由单倍体以及正常二倍体诱导。这使得Pombe在阐明启动重组的基本原理方面特别有用，而没有更复杂的生物的并发症。此外，作为染色体行为的模型，裂变酵母已被确立，并具有完整的工具和技术集合。第一个目标询问细胞在减数分裂过程中如何修饰其正常损伤反应，因为CHK1检查点激酶途径在减数分裂过程中未激活。该目标将使用遗传，分子和细胞生物学方法来检查CHK1途径如何中断并确定负责的任何新因素。第二个目标询问复制激酶HSK1（CDC7）如何在减数分裂中起作用，以促进双链断裂和正确的染色体分离。这项研究将为减数分裂分化过程中基因组稳定性机制提供重要的见解。