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Differential mitotic checkpoint protein requirements in somatic and germ cells
K B Jeganathan1, J M van Deursen
1Department of Pediatric and Adolescent Medicine, Mayo College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
Abstract:
Cdc20 (cell division cycle 20) and Cdh1 are the activating subunits of APC (anaphase-promoting complex), an E3-ubiquitin ligase that drives cells into anaphase by inducing degradation of cyclin B and the anaphase inhibitor securin. To prevent chromosome missegregation due to early degradation of cyclin B and securin, mitotic checkpoint protein complexes consisting of BubR1, Bub3 and Mad2 bind to and inhibit APC(Cdc20) until all chromosomes are properly attached to the mitotic spindle and aligned in the metaphase plate. The nuclear transport factors Rae1 and Nup98, which convert into mitotic checkpoint proteins in M-phase, further prevent chromosome missegregation by assembling into a complex with APC(Cdh1) and delaying APC(Cdh1)-mediated ubiquitination of securin. Disruption of Mad2, BubR1, Bub3 or Rae1 in mice results in substantial aneuploidy in somatic tissues, but whether these genes are equally important for accurate chromosome segregation during meiosis has not yet been established. To address this issue, we generated cohorts of male mice in which Mad2, BubR1, Bub3, Rae1 and Nup98 were disrupted either individually or in combination. We tested the fertility of these mice and performed chromosome counts on secondary spermatocytes. We found that male fertility and accurate chromosome segregation during spermatogenesis are highly dependent on BubR1, but not Mad2, Bub3, Rae1 and Nup98. Our results suggest that the mechanisms ensuring accurate chromosome segregation differ between mitotic and meiotic cells.
Insights
Accurate chromosome segregation during male meiosis is crucial and depends heavily on BubR1. Unlike in mitosis, Mad2, Bub3, Rae1, and Nup98 are not essential for this process in spermatogenesis.
Area of Science:
- Cell Biology
- Genetics
- Reproductive Biology
Background:
- The anaphase-promoting complex (APC), activated by Cdc20 or Cdh1, regulates cell division by degrading key proteins.
- Mitotic checkpoint proteins (BubR1, Bub3, Mad2) and nuclear transport factors (Rae1, Nup98) prevent chromosome missegregation during mitosis.
- Previous studies showed aneuploidy in mice lacking Mad2, BubR1, Bub3, or Rae1, but their role in meiosis was unclear.
Purpose of the Study:
- To investigate the roles of Mad2, BubR1, Bub3, Rae1, and Nup98 in ensuring accurate chromosome segregation during male meiosis.
- To determine if these proteins have differential importance in mitosis versus meiosis.
Main Methods:
- Generated male mice with individual or combined disruptions of Mad2, BubR1, Bub3, Rae1, and Nup98.
- Assessed male fertility and performed chromosome counts on secondary spermatocytes to evaluate meiotic accuracy.
Main Results:
- Male fertility and accurate chromosome segregation during spermatogenesis were found to be highly dependent on BubR1.
- Disruption of Mad2, Bub3, Rae1, or Nup98 did not significantly impair male fertility or meiotic chromosome segregation.
- These findings indicate a differential requirement for these proteins between mitotic and meiotic cell division.
Conclusions:
- BubR1 plays a critical role in maintaining genomic stability during male meiosis.
- The mechanisms ensuring accurate chromosome segregation differ significantly between mitotic and meiotic cell cycles.
- This study highlights the specialized roles of checkpoint proteins in different cell division contexts.
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