Checkpoints and double strand breaks in S. pombe meiosis

减数分裂是一种特殊的细胞分裂过程，常见于有性生殖的真核生物，将二倍体受精卵减少到重组的单倍体配子。减数分裂缺陷对人类健康有着深远的影响。超过一半的人类流产是由于严重的染色体异常造成的，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是理解人类生殖的基础。减数分裂的一个重要组成部分是程序性断裂的产生，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，这必须在适当的时间内进行，以促进交叉。本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，到在减数分裂早期的调节程序中主动破坏基因组。广泛的假设是，在减数分裂中，调节S期正常进程的激酶被采用，以允许重组断裂发生。模式生物的选择是关键。分裂酵母有一个简单的减数分裂，它可以从单倍体和正常的二倍体诱导。这使得S. pombe在阐明启动重组的基本原理方面特别有用，而不需要更复杂生物体的复杂性。此外，裂变酵母作为染色体行为的模型已经很好地建立起来，并且拥有完整的工具和技术集合。第一个目标是询问细胞在减数分裂期间如何修改其正常损伤反应，因为Chk1检查点激酶途径在减数分裂期间未被激活。该目标将使用遗传，分子和细胞生物学方法来检查Chk1途径是如何中断的，并确定任何新的因素。第二个目的是研究复制激酶Hsk1 （Cdc7）如何在减数分裂中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的机制提供重要的见解。

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.