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The roles of MAD1, MAD2 and MAD3 in meiotic progression and the segregation of nonexchange chromosomes


Errors in meiotic chromosome segregation are the leading cause of spontaneous abortions and birth defects1. In humans, chromosomes that fail to experience crossovers (or exchanges) are error-prone, more likely than exchange chromosomes to mis-segregate in meiosis. We used a yeast model to investigate the mechanisms that partition nonexchange chromosomes. These studies showed that the spindle checkpoint genes MAD1, MAD2 and MAD3 have different roles. We identified a new meiotic role for MAD3; though dispensable for the segregation of exchange chromosomes, it is essential for the segregation of nonexchange chromosomes. This function of Mad3p could also be carried out by human BubR1. MAD1 and MAD2 act in a surveillance mechanism that mediates a metaphase delay in response to nonexchange chromosomes, whereas MAD3 acts as a crucial meiotic timer, mediating a prophase delay in every meiosis. These findings suggest plausible models for the basis of errant meiotic segregation in humans.

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Figure 1: Recombination and chromosome segregation in meiosis.
Figure 2: Mad3p is crucial for the segregation of nonexchange chromosomes.
Figure 3: Mad3p imposes a delay in passage through meiosis I.
Figure 4: Model for timing of Mad1p-, Mad2p- and Mad3p-mediated delays.

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We thank M. Shonn Dorer, B. McCarroll, A. Murray and A. Straight for providing key reagents and for many discussions of this work; M. Stewart for critical reading of the manuscript; members of the laboratory of D.S.D. for their contributions to the project; T. Stearns and M. Winey for antibodies to Tub4; F. McKeon for hBubR1 clones; and S. Acharya and A. Parmalee for assistance with flow cytometry. This research was supported by a grant from the March of Dimes.

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Correspondence to Dean S Dawson.

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Supplementary Table 1

Strains used in this study. (PDF 106 kb)

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Cheslock, P., Kemp, B., Boumil, R. et al. The roles of MAD1, MAD2 and MAD3 in meiotic progression and the segregation of nonexchange chromosomes. Nat Genet 37, 756–760 (2005).

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