Mad3p Promotes Non-exchange Chromosome Segregation Fidelity and Delays Anaphase Onset in Meiosis I of Saccharomyces Cerevisiae
Errors in meiotic chromosome segregation are the leading cause of spontaneous abortions and birth defects. In humans, chromosomes that fail to experience crossovers (exchanges) are error-prone, more likely than exchange chromosomes to mis-segregate in meiosis. We employed a yeast model to investigate the mechanisms that partition non-exchange chromosomes. These studies demonstrated differential roles for the spindle checkpoint genes MAD1, MAD2 and MAD3. We identified a novel meiotic role for MAD3; though dispensable for the segregation of exchange chromosomes, it is essential for the segregation of non-exchange chromosomes. MAD1 and MAD2 were found to act in a surveillance mechanism that mediates a metaphase delay in response to non-exchange chromosomes, while MAD3 acts as a crucial meiotic timer, mediating a prophase delay in every meiosis. Importantly the function of MAD3 could be complemented byBUB1B, the human homolog of MAD3. Attempts to complement the Mad3p-mediated delay failed to rescue non-exchange chromosome segregation. While we could not identify the mechanism for Mad3p function in meiosis, our results implicate a target other than CDC20 family members. These findings imply a plausible model for the basis of errant meiotic segregation in humans.
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Table of Contents
Human Segregation Errors
What is the Checkpoint monitoring?
Establishing the Checkpoint
Meiotic time course
The Roles of Mad1 Mad2 and Mad3 in Meiotic Progression
Multiple roles for Mad3p in meiotic cell cycle progression in yeast
Summary of Results
All delays are not created equally
affect chromosome segregation alleles AMA1 anaphase aneuploidy APC/C arg4-AHpa arrest Auxotrophic B-type benomyl BUB1B Bub1p Bub3p BubR1 budding yeast carlsbergensis CDC20 family members cell cycle cell cycle progression cells lacking centromere cerevisiae chromosome segregation fidelity chromosomes were scored cyclin defects deletion described in Chapter diagnostic digest Diploid DNA damage checkpoint evaluated exchange chromosomes Figure haploid Hardwick HIS3 his3-Al homologous hydroxyurea ilvl-Kpn inhibition Iys2-AB KEN box kinetochores LEU2 lacO listed were sporulated live spores containing MAD1 Mad1p and Mad2p mad2 MAD3 mad3 mutants Mad3p Mad3p function Mad3p-mediated delay MATa MCK1 mediated gene replacement meiosis metaphase microtubule mitosis mitotic mutants non-exchange chromosome pair non-exchange chromosome segregation non-exchange pair nondisjunction nondisjunction events over-expression PCR mediated gene PCR product Pds1p plasmid PrCYc-GFP-/ac primers proper segregation prophase proteins rad3 recombination scored as nondisjunction segregation errors segregation of non-exchange spindle checkpoint function spindle checkpoint genes spores sporulation sporulation medium suggest synapsis tetrad dissection trp2