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.
Defects in meiosis have profound consequences for human health. More than 20% of human conceptions end in miscarriage, half of which have gross chromosomal abnormalities. A large fraction of these abnormalities result from errors during meiotic chromosome replication, recombination, or segregation, predominantly in females. The mechanisms that monitor and regulate chromosome processes during meiosis are therefore fundamental to the health of human gametes. Because the proteins involved in meiotic DNA replication and recombination are highly conserved from yeast to humans, the insights gained from model systems are directly relevant to understanding these events in human cells. This proposal focuses on two conserved protein kinases, Chk1 and Hsk1(Cdc7), which are intimately linked to genome stability during vegetative growth, and investigates how their function in genome protection changes during meiosis.
