In humans, errors in meiosis I are the leading cause of birth defects, mental retardation, and a significant contributor to infertility. In meiosis I, chromosomes exhibit a unique segregation pattern; sister chromatids remain together, while homologous chromosomes segregate from each other. Human aneuploidy sometimes occurs because sister chromatids separate in meiosis I, as they do in mitosis. Other times aneuploidy occurs because homologous partners segregate to the same side of the spindle at meiosis I. The correct meiotic segregation pattern is achieved by meiosis-specific mechanisms that alter chromosome structures and the cell cycle control of segregation. First, meiosis I segregation is accomplished by tethering the homologous chromosomes through recombination so they will act as segregation partners. Second, kinetochores are altered, and centromeric cohesins are protected from removal, so sister chromatids remain joined. Third, a previously unrecognized process, homologous centromere pairing (CEN-pairing), holds the centomeres together in ways that help them orient on the spindle. Fourth, the assembly of the spindle is delayed so the formation of meiotic chromosome pairs can be completed before the chromosomes begin segregating. Failures in any of these meiotic modifications to chromosome behavior could be culprits in human meiotic segregation errors. The experiments proposed here focus on these meiosis-specific processes and adress: How are meiosis I kinetochores assembled so that sister chromatids will segregate as a unit? What is the basis for CEN-pairing? How is spindle assembly coordinated with chromosome behavior to allow proper completion of the re-structuring of meiotic centromeres? The proposal is divided into three sets of experiments. The experiments use budding yeast as a model organism and a combination of molecular genetic, cell imaging and biochemical approaches. The first set of experiments will explore how the cell disassembles the kineotchores that are on chromosomes when meiosis begins, and replaces them with kinetochores that will dictate meiosis I segregation behaviors. These experiments will employ mass spectrometry methods that will allow assessment of overall kinetochore composition as cells progress through meiosis I, and complementary imaging approaches that will examine behaviors of individual kinetochore components. The second set of experiments will examine how CEN-pairing is accomplished. CEN-pairing requires the synaptonemal complex (SC) protein, Zip1, which persists at the paired centromeres after SC disassembly. The final set of experiments employs genetic methods to determine how chromosome and spindle dynamics are coordinated in meiosis so that spindle formation is blocked until chromosomes have properly identified and paired with their segregation partners. Completion of the proposed experiments will elucidate how meiotic remodeling of kinetochore structures, and centromere and spindle behaviors, allows homologous chromosomes to be segregated with high fidelity in meiosis I.

Public Health Relevance

Errors in the process of distributing chromosomes to the gametes is the major cause of birth defects and mental retardation, and is a major contributor to infertility. This project uses buddin yeast to identify undiscovered ways in which a component of the chromosome, called the centromere, might help direct chromosomes movements, in doing so, helping to prevent the errors that lead to birth defects

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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Oklahoma Medical Research Foundation
Oklahoma City
United States
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Meyer, Régis E; Brown, Jamin; Beck, Lindsay et al. (2018) Mps1 promotes chromosome meiotic chromosome biorientation through Dam1. Mol Biol Cell 29:479-489
Kurdzo, Emily L; Chuong, Hoa H; Evatt, Jared M et al. (2018) A ZIP1 separation-of-function allele reveals that centromere pairing drives meiotic segregation of achiasmate chromosomes in budding yeast. PLoS Genet 14:e1007513
Kurdzo, Emily L; Obeso, David; Chuong, Hoa et al. (2017) Meiotic Centromere Coupling and Pairing Function by Two Separate Mechanisms in Saccharomyces cerevisiae. Genetics 205:657-671
Rankin, Susannah; Dawson, Dean S (2016) Recent advances in cohesin biology. F1000Res 5:
Kurdzo, Emily L; Dawson, Dean S (2015) Centromere pairing--tethering partner chromosomes in meiosis I. FEBS J 282:2458-70
Meyer, Régis E; Chuong, Hoa H; Hild, Marrett et al. (2015) Ipl1/Aurora-B is necessary for kinetochore restructuring in meiosis I in Saccharomyces cerevisiae. Mol Biol Cell 26:2986-3000
Obeso, David; Pezza, Roberto J; Dawson, Dean (2014) Couples, pairs, and clusters: mechanisms and implications of centromere associations in meiosis. Chromosoma 123:43-55
Kim, Seoyoung; Meyer, Régis; Chuong, Hoa et al. (2013) Dual mechanisms prevent premature chromosome segregation during meiosis. Genes Dev 27:2139-46
Meyer, Régis E; Dawson, Dean S (2013) Attaching to spindles before they form: do early incorrect chromosome-microtubule attachments promote meiotic segregation fidelity? Cell Cycle 12:2011-5
Meyer, Regis E; Kim, Seoyoung; Obeso, David et al. (2013) Mps1 and Ipl1/Aurora B act sequentially to correctly orient chromosomes on the meiotic spindle of budding yeast. Science 339:1071-4

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