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A phosphate-binding pocket in cyclin B3 is essential for XErp1/Emi2 degradation in meiosis I

ABSTRACT: To ensure the correct euploid state of embryos, it is essential that vertebrate oocytes await fertilization arrested at metaphase of meiosis II. This MII arrest is mediated by XErp1/Emi2, which inhibits the ubiquitin ligase APC/C (anaphase-promoting complex/cyclosome). Cyclin B3 in complex with Cdk1 (cyclin-dependent kinase 1) is essential to prevent an untimely arrest of vertebrate oocytes in meiosis I by targeting XErp1/Emi2 for degradation. Yet, the molecular mechanism of XErp1/Emi2 degradation in MI is not well understood. Here, by combining TRIM-Away in oocytes with egg extract and in vitro studies, we demonstrate that a hitherto unknown phosphate-binding pocket in cyclin B3 is essential for efficient XErp1/Emi2 degradation in meiosis I. This pocket enables Cdk1/cyclin B3 to bind pre-phosphorylated XErp1/Emi2 facilitating further phosphorylation events, which ultimately target XErp1/Emi2 for degradation in a Plk1 (Polo-like kinase 1) dependent manner. Key elements of this degradative mechanism are conserved in frog and mouse. Our studies identify a novel, evolutionarily conserved determinant of Cdk/cyclin substrate specificity essential to prevent an untimely oocyte arrest at meiosis I with catastrophic consequences upon fertilization.

SUBMITTER: Ms. Rebecca Schunk

PROVIDER: S-SCDT-10_1038-S44319-024-00347-8 | biostudies-other |

REPOSITORIES: biostudies-other

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Cyclin B3 promotes anaphase I onset in oocyte meiosis.

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Maternal EHMT2 is essential for homologous chromosome segregation by regulating <i>Cyclin B3</i> transcription in oocyte meiosis.

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Phosphate-binding pocket on cyclin B governs CDK substrate phosphorylation and mitotic timing - NCOMMS-24-17810-T - 2

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Maternal EHMT2 is essential for homologous chromosome segregation by regulating Cyclin B3 in mouse oocytes

Project description:During oocyte growth, various epigenetic modifications gradually establish, accompanying by large amounts of mRNAs and proteins accumulate. However, progress has been slow regarding the relationship between epigenetic modification and meiosis. Here, using Gdf9-Cre to achieve oocyte-specific ablation of Ehmt2 (Euchromatic Histone Lysine Methyltransferase 2) from primordial follicle stage, we found that female mutant mice were infertile and oocyte-specific knockout of Ehmt2 caused the failure of homologous chromosome separation independent of persistently activated SAC during the first meiosis. Further studies revealed that lacking maternal Ehmt2 affected the transcriptional level of Ccnb3, and microinjection of exogenous Ccnb3 mRNA could partly rescue the failure of homologous chromosomes segregation. Of particular importance was that EHMT2 could directly interact with CCNB3, despite truncated the SET domain. Therefore, our findings highlight the novel function of maternal EHMT2 on the metaphase I-to-anaphase I transition in mouse oocyte: directly interacting with CCNB3 apart from regulating the transcription of Ccnb3.

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