During the mitotic cell cycle a single round of DNA replication is followed by a chromosome segregation phase. Meiosis is a specialized cell cycle in which a single DNA replication phase is followed by two consecutive chromosome segregation phases. During the first meiotic division (meiosis I), homologous chromosomes are segregated whereas during the second meiotic division (meiosis II) sister chromatids are divided. Meiosis-specific regulators of chromosome segregation are likely to act on the machinery common to mitotic and meiotic chromosome segregation, to bring about the meiotic chromosome segregation program. We propose to study two aspects of this unusual cell cycle. First, we will examine the transition between the first and the second meiotic division, during which conditions are established that facilitate a second round of chromosome segregation rather than DNA replication. Second, we will examine how the unusual meiosis I chromosome segregation pattern is established. To determine how the meiosis I - meiosis II transition is controlled we will characterize the function of the protein phosphatase Cdc14, which has been shown to control the analogous transition, the mitosis - G1 transition during the mitotic cell cycle. We will assess how Cdc14 controls the meiosis I - meiosis II transition and determine how Cdc14 is itself regulated during meiosis. Two approaches will be taken to characterize the events necessary to establish the meiosis I chromosome segregation pattern. (1) We will determine how Spo13, a protein known to regulate meiotic chromosome segregation, regulates this process. (2) We will characterize the role of genes we recently identified through a genetic screen, in establishing the meiosis I chromosome segregation. Chromosome mis-segregation during meiosis is a leading cause of birth defects and the leading cause of miscarriages in humans. It is, therefore, vital to understand the molecular mechanisms that regulate the meiotic cell cycle to open avenues towards the development of diagnostics and therapeutics. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM062207-05A1
Application #
7027958
Study Section
Nuclear Dynamics and Transport (NDT)
Program Officer
Zatz, Marion M
Project Start
2001-03-01
Project End
2009-11-30
Budget Start
2005-12-01
Budget End
2006-11-30
Support Year
5
Fiscal Year
2006
Total Cost
$263,821
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Internal Medicine/Medicine
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Santaguida, Stefano; Richardson, Amelia; Iyer, Divya Ramalingam et al. (2017) Chromosome Mis-segregation Generates Cell-Cycle-Arrested Cells with Complex Karyotypes that Are Eliminated by the Immune System. Dev Cell 41:638-651.e5
Weidberg, Hilla; Moretto, Fabien; Spedale, Gianpiero et al. (2016) Nutrient Control of Yeast Gametogenesis Is Mediated by TORC1, PKA and Energy Availability. PLoS Genet 12:e1006075
Berchowitz, Luke E; Kabachinski, Greg; Walker, Margaret R et al. (2015) Regulated Formation of an Amyloid-like Translational Repressor Governs Gametogenesis. Cell 163:406-18
Berchowitz, Luke E; Gajadhar, Aaron S; van Werven, Folkert J et al. (2013) A developmentally regulated translational control pathway establishes the meiotic chromosome segregation pattern. Genes Dev 27:2147-63
Attner, Michelle A; Miller, Matthew P; Ee, Ly-sha et al. (2013) Polo kinase Cdc5 is a central regulator of meiosis I. Proc Natl Acad Sci U S A 110:14278-83
Miller, Matthew P; Amon, Angelika; Ünal, Elçin (2013) Meiosis I: when chromosomes undergo extreme makeover. Curr Opin Cell Biol 25:687-96
Attner, Michelle A; Amon, Angelika (2012) Control of the mitotic exit network during meiosis. Mol Biol Cell 23:3122-32
van Werven, Folkert J; Neuert, Gregor; Hendrick, Natalie et al. (2012) Transcription of two long noncoding RNAs mediates mating-type control of gametogenesis in budding yeast. Cell 150:1170-81
Miller, Matthew P; Unal, Elçin; Brar, Gloria A et al. (2012) Meiosis I chromosome segregation is established through regulation of microtubule-kinetochore interactions. Elife 1:e00117
Ünal, E; Amon, A (2011) Gamete formation resets the aging clock in yeast. Cold Spring Harb Symp Quant Biol 76:73-80

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