Abstract PR11: APC/CCdh1 maintains primordial follicles, germinal vesicle arrest and ensures balanced segregation of chromosomes by enabling removal of Shugoshin-2 from chromosomes arms

Abstract

Abstract Germ cells in mammals, including humans, remain arrested at the primordial follicle stage from a few days to many years depending on the species. At each hormonal cycle, a few of these cells grow in size to become fully-grown oocytes but remain arrested in meiotic prophase. A resumption of meiosis is heralded by germinal vesicle breakdown (GVBD), a gradual rise in Cdk1 activity, condensation of bivalent chromosomes, and their eventual alignment on metaphase plates with maternal and paternal kinetochore pairs pulled in opposite directions (co-orientation). The first meiotic division is triggered by activation of a form of the Anaphase-promoting complex/cyclosome associated with Cdc20 (APC/CCdc20), which activates separase and thereby destroys sister chromatid cohesion along chromosome arms, resolving chiasmata. Because cohesion around centromeres is protected from separase by protein phosphatase 2A (PP2A) recruited by shugoshin (Sgol2), bivalents are converted at this division to dyad chromosomes in which sister chromatids are held together by peri-centric cohesin. We show here that an alternative version of the APC/C associated with the Cdc20-like Cdh1 protein (APC/CCdh1) has equally important roles. By promoting proteolysis of mitotic cyclins and Cdc25B, APC/CCdh1 delays the increase in Cdk1 activity leading to GVBD. More surprising, by moderating the rate at which Cdk1 is activated following GVBD, APC/CCdh1 creates conditions necessary for the removal of Sgol2 from chromosome arms by the Aurora B/C kinase, an event crucial for the efficient resolution of chiasmata. Lastly, by targeting proteins other than cyclins, APC/CCdh1 prevents apoptosis of primordial follicles during their extended prophase (G2) arrest. This abstract is also being presented as Poster A24. Citation Format: Ahmed Rattani, Randy Ballestros Mejia, Katherine Roberts, Maurici B Roig, Jonathan Godwin, Manuel Eguren, Sugako Ogushi, Elwy Okaz, Alberto Pendas, Malumbres Marcos, Mary Herbert, Kim Nasmyth. APC/CCdh1 maintains primordial follicles, germinal vesicle arrest and ensures balanced segregation of chromosomes by enabling removal of Shugoshin-2 from chromosomes arms. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr PR11.