Mnd2, an Essential Antagonist of the Anaphase-Promoting Complex during Meiotic Prophase

Abstract

Meiotic cohesin serves in sister chromatid linkage and DNA repair until its subunit Rec8 is cleaved by separase. Separase is activated when its inhibitor, securin, is polyubiquitinated by the Cdc20 regulated anaphase-promoting complex (APC(Cdc20)) and consequently degraded. Differently regulated APCs (APC(Cdh1), APC(Ama1)) have not been implicated in securin degradation at meiosis I. We show that Mnd2, a factor known to associate with APC components, prevents premature securin degradation in meiosis by APC(Ama1). mnd2Delta cells lack linear chromosome axes and exhibit precocious sister chromatid separation, but deletion of AMA1 suppresses these defects. Besides securin, Sgo1, a protein essential for protection of centromeric cohesion during anaphase I, is also destabilized in mnd2delta cells. Mnd2's disappearance prior to anaphase II may activate APC(Ama1). Human oocytes may spend many years in meiotic prophase before maturation. Inhibitors of meiotic APC variants could prevent loss of chiasmata also in these cells, thereby guarding against aberrant chromosome segregation.

Sporulation in the Budding Yeast Saccharomyces cerevisiae

“…AMA1 encodes a sporulation-specific member of the Cdc20 family (Cooper et al 2000). Though expressed as an early-middle gene, its activity is repressed early in meiosis by CDK phosphorylation and by another APC subunit, Mnd2, which leaves the APC during meiosis II (Oelschlaegel et al 2005;Penkner et al 2005). If this regulation is disrupted (e.g., in mnd2D mutants), premature activation of APC-Ama1 leads to defects in chromosome segregation (Oelschlaegel et al 2005;Penkner et al 2005).…”

“…Though expressed as an early-middle gene, its activity is repressed early in meiosis by CDK phosphorylation and by another APC subunit, Mnd2, which leaves the APC during meiosis II (Oelschlaegel et al 2005;Penkner et al 2005). If this regulation is disrupted (e.g., in mnd2D mutants), premature activation of APC-Ama1 leads to defects in chromosome segregation (Oelschlaegel et al 2005;Penkner et al 2005). Though there is some evidence for an Ama1 function during meiosis, the combined action of Mnd2 and CDK likely limits the primary functions of APCAma1 to the end of meiosis II (Cooper et al 2000;Oelschlaegel et al 2005;Tan et al 2010).…”

“…Though AMA1 is induced as a pre-middle gene, the activity of APC-Ama1 is restricted by the action of the APC subunit Mnd2 and by Clb-CDK phosphorylation, so that it does not become fully active until late in meiosis II (Oelschlaegel et al 2005;Penkner et al 2005). As described earlier, once APC-Ama1 is active, it leads to degradation of the leading edge protein Ssp1 (though direct Ama1-dependent ubiquitylation of Ssp1 has not been demonstrated) and this serves to link membrane closure to the end of meiosis (Diamond et al 2008).…”

Keeping sister chromatids together: cohesins in meiosis

“…Certainly, shugoshin is not the only protector of cohesion in meiosis. Other factors, such as Mnd2, a meiosis-specific antagonist of APC/C (Oelschaegel et al 2005, Penkner et al 2005, or Spo13, which is involved in the maintenance of centromeric cohesion in meiosis I ( Katis et al 2004, Lee et al 2004, were recently characterized in yeast, and they also contribute to the maintenance of centromeric cohesion. Similar mammalian meiosis-specific regulators of cohesion remain to be discovered.…”

The Ras/cAMP Pathway and the CDK-Like Kinase Ime2 Regulate the MAPK Smk1 and Spore Morphogenesis in Saccharomyces cerevisiae

“…Positive regulators of Smk1 activation include Ama1 (McDonald et al 2005), a meiosis-specific Cdc20-family member that links substrates to the APC (Cooper et al 2000). It has been proposed that the APC Ama1 plays a role in coupling completion of the meiotic divisions to gamete formation (Oelschlaegel et al 2005;Penkner et al 2005). Ssp2, a middle meiosis-specific protein that regulates spore formation (Sarkar et al 2002;Coluccio et al 2004;Li et al 2007) is also required for efficient phosphorylation of Smk1's activation loop (McDonald et al 2005).…”