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.

Public Health Relevance

Birth defects and miscarriages result from mistakes in the specialized cell division process called meiosis, and rates of these mistakes increase with age. An important step in meiosis is genetic recombination, which is required for faithful separation of chromosomes. This project uses a simple model organism, fission yeast, to examine how recombination is regulated to ensure faithful chromosome segregation and viability of the offspring.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular Genetics A Study Section (MGA)
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Hagan, Ann A
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University of Southern California
Schools of Arts and Sciences
Los Angeles
United States
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Escorcia, Wilber; Forsburg, Susan L (2017) Destabilization of the replication fork protection complex disrupts meiotic chromosome segregation. Mol Biol Cell 28:2978-2997
Ranatunga, Nimna S; Forsburg, Susan L (2016) Characterization of a Novel MMS-Sensitive Allele of Schizosaccharomyces pombe mcm4. G3 (Bethesda) 6:3049-3063
Sabatinos, Sarah A; Ranatunga, Nimna S; Yuan, Ji-Ping et al. (2015) Replication stress in early S phase generates apparent micronuclei and chromosome rearrangement in fission yeast. Mol Biol Cell 26:3439-50
Sabatinos, Sarah A; Forsburg, Susan L (2015) Managing Single-Stranded DNA during Replication Stress in Fission Yeast. Biomolecules 5:2123-39
Ding, Lin; Forsburg, Susan L (2014) Essential domains of Schizosaccharomyces pombe Rad8 required for DNA damage response. G3 (Bethesda) 4:1373-84
Mastro, Tara L; Forsburg, Susan L (2014) Increased meiotic crossovers and reduced genome stability in absence of Schizosaccharomyces pombe Rad16 (XPF). Genetics 198:1457-72
Ding, Lin; Laor, Dana; Weisman, Ronit et al. (2014) Rapid regulation of nuclear proteins by rapamycin-induced translocation in fission yeast. Yeast 31:253-64
Le, Anh-Huy; Mastro, Tara L; Forsburg, Susan L (2013) The C-terminus of S. pombe DDK subunit Dfp1 is required for meiosis-specific transcription and cohesin cleavage. Biol Open 2:728-38
Sabatinos, Sarah A; Mastro, Tara L; Green, Marc D et al. (2013) A mammalian-like DNA damage response of fission yeast to nucleoside analogs. Genetics 193:143-57
Dolan, William P; Le, Anh-Huy; Schmidt, Henning et al. (2010) Fission yeast Hsk1 (Cdc7) kinase is required after replication initiation for induced mutagenesis and proper response to DNA alkylation damage. Genetics 185:39-53