Meiosis is a specialized cell division program that gives rise to gametes in sexually reproducing organisms. The first stage of meiosis, called meiosis I, uniquely involves the association, programmed recombination, and eventual segregation of homologous chromosomes. While this process is well understood from a genetic and cytological standpoint, our understanding of how the meiosis-specific cellular machinery is able to organize and manipulate meiotic chromosomes in 3D space to mediate their proper segregation remains a mystery. This area of study is significant, as errors in meiosis I chromosome segregation account for the vast majority of aneuploidies, extra or missing chromosomes in offspring, that occur in over half of human oocytes and 5-10% of clinically recognized pregnancies. As such, aneuploidy is the leading genetic cause of miscarriage and of mental retardation (e.g. Down syndrome, caused by trisomy of chromosome 21). The underlying causes of chromosome segregation errors in meiosis I are not well understood, and further progress toward identifying these causes will require a detailed understanding of the molecular mechanisms of meiosis-specific chromosome segregation machinery. Here, we propose to study three sets of meiotic chromosome-associated proteins that are critical for different aspects of chromosomes'organization and physical manipulation in meiosis I. Our approach combines in vitro reconstitution of purified proteins and complexes, 3D structural analysis of these complexes, and targeted genetic assays to test mutants designed to disrupt specific aspects of these proteins'structures and interactions. We will first study the S. cerevisiae monopolin complex, which binds chromosomes'kinetochores in meiosis I and modifies their attachments to spindle microtubules, to enable the proper orientation and segregation of homologous chromosomes. We will determine the architecture of the monopolin complex, and use engineered protein constructs in genetic assays to test whether it directly cross-links sister kinetochores to mediate their attachment to a single microtubule. Next, we will study the conserved chromosome-associated protein Hop1, a component of the proteinaceous """"""""axis"""""""" about which each chromosome is organized. We will examine the roles of Hop1's conserved HORMA domain, a signaling domain shared with the spindle checkpoint protein Mad2, in regulating inter-homolog meiotic recombination, and in a meiosis-specific checkpoint monitoring recombination. Finally, we will study the synaptonemal complex, an essential polymeric assembly that links homologs together during meiotic recombination. As very little is known about the architecture of this complex or its functions, we will study the domain structure, protein-protein interactions, and self-assembly determinants of the key S. cerevisiae synaptonemal complex protein Zip1. Combined, this work will begin to provide a more accurate picture of the macromolecular structures and interactions underlying homologous chromosome recombination and segregation in meiosis I.

Public Health Relevance

The proposed project is highly relevant to public health, in that it investigates a process whose failure can result in infertility, miscarriage, and developmental disorders in children. Our work focuses on meiosis, the cell division program that gives rise to gametes in sexual reproduction, and particularly we concentrate on how cells segregate their chromosomes properly in meiosis to avoid aneuploidy. Aneuploidy, characterized by the gain or loss of one or more chromosomes in an embryo, occurs in 5-10% of clinically recognized pregnancies, and causes miscarriage or developmental disorders like Down syndrome. Our work to characterize the molecular mechanisms ensuring proper chromosome segregation during gamete formation could eventually enable therapies to reduce the prevalence of aneuploidy in embryos, and increase fertility in individuals with defects in the relevant cellular machinery.

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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Janes, Daniel E
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Ludwig Institute for Cancer Research Ltd
La Jolla
United States
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West, Alan M V; Komives, Elizabeth A; Corbett, Kevin D (2018) Conformational dynamics of the Hop1 HORMA domain reveal a common mechanism with the spindle checkpoint protein Mad2. Nucleic Acids Res 46:279-292
Singh, Namit; Corbett, Kevin D (2018) The budding-yeast RWD protein Csm1 scaffolds diverse protein complexes through a conserved structural mechanism. Protein Sci 27:2094-2100
Kim, Dong Hyun; Han, Joo Seok; Ly, Peter et al. (2018) TRIP13 and APC15 drive mitotic exit by turnover of interphase- and unattached kinetochore-produced MCC. Nat Commun 9:4354
Ye, Qiaozhen; Kim, Dong Hyun; Dereli, Ihsan et al. (2017) The AAA+ ATPase TRIP13 remodels HORMA domains through N-terminal engagement and unfolding. EMBO J 36:2419-2434
Corbett, Kevin D (2017) Molecular Mechanisms of Spindle Assembly Checkpoint Activation and Silencing. Prog Mol Subcell Biol 56:429-455
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Liang, Jason; Singh, Namit; Carlson, Christopher R et al. (2017) Recruitment of a SUMO isopeptidase to rDNA stabilizes silencing complexes by opposing SUMO targeted ubiquitin ligase activity. Genes Dev 31:802-815
Ye, Qiaozhen; Ur, Sarah N; Su, Tiffany Y et al. (2016) Structure of the Saccharomyces cerevisiae Hrr25:Mam1 monopolin subcomplex reveals a novel kinase regulator. EMBO J 35:2139-2151
Meyer, Peter A; Socias, Stephanie; Key, Jason et al. (2016) Data publication with the structural biology data grid supports live analysis. Nat Commun 7:10882
Rosenberg, Scott C; Corbett, Kevin D (2015) The multifaceted roles of the HORMA domain in cellular signaling. J Cell Biol 211:745-55

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