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：
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
项目类别：
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

项目摘要

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.

减数分裂是有性生殖真核生物常见的一种特殊的细胞分裂过程，它将二倍体合子减少为重组单倍体配子。减数分裂缺陷对人类健康具有深远的影响。超过一半的人类流产是由严重的染色体异常引起的，其中大部分是由于减数分裂过程中的错误造成的。因此，了解减数分裂期间的染色体事件对于了解人类生殖至关重要。减数分裂的一个重要组成部分是产生程序性断裂以启动重组和遗传信息的交换。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，必须适当安排时间以促进交叉。该项目研究细胞如何改变其检查点反应，从保护基因组和防止随机双链断裂，到在减数分裂早期阶段的调控程序中主动破坏基因组。广泛的假设是，调节 S 期正常进展的激酶在减数分裂中被选择，以允许发生重组断裂。模式生物的选择是关键。裂殖酵母具有简单的减数分裂，可以由单倍体以及正常的二倍体诱导。这使得粟酒裂殖酵母在阐明启动重组的基本原理方面特别有用，而且不会产生更复杂生物体的并发症。此外，裂殖酵母作为染色体行为的模型已得到很好的建立，并拥有完整的工具和技术。第一个目标是询问细胞如何在减数分裂过程中修改其正常损伤反应，因为 Chk1 检查点激酶通路在减数分裂过程中并未激活。这一目标将使用遗传、分子和细胞生物学方法来检查 Chk1 通路是如何被中断的，并找出任何新的相关因素。第二个目标是了解复制激酶 Hsk1 (Cdc7) 在减数分裂中如何发挥作用，促进双链断裂和适当的染色体分离。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见解。