Cyclin B3 activates the Anaphase-Promoting Complex/Cyclosome in meiosis and mitosis

Abstract

In mitosis and meiosis, chromosome segregation is triggered by the Anaphase-Promoting Complex/Cyclosome (APC/C), a multi-subunit ubiquitin ligase that targets proteins for degradation, leading to the separation of chromatids. APC/C activation requires phosphorylation of its APC3 and APC1 subunits, which allows the APC/C to bind its co-activator Cdc20. The identity of the kinase(s) responsible for APC/C activation in vivo is unclear. Cyclin B3 (CycB3) is an activator of the Cyclin-Dependent Kinase 1 (Cdk1) that is required for meiotic anaphase in flies, worms and vertebrates. It has been hypothesized that CycB3-Cdk1 may be responsible for APC/C activation in meiosis but this remains to be determined. Using Drosophila, we found that mutations in CycB3 genetically enhance mutations in tws, which encodes the B55 regulatory subunit of Protein Phosphatase 2A (PP2A) known to promote mitotic exit. Females heterozygous for CycB3 and tws loss-of-function alleles lay embryos that arrest in mitotic metaphase in a maternal effect, indicating that CycB3 promotes anaphase in mitosis in addition to meiosis. This metaphase arrest is not due to the Spindle Assembly Checkpoint (SAC) because mutation of mad2 that inactivates the SAC does not rescue the development of embryos from CycB3-/+, tws-/+ females. Moreover, we found that CycB3 promotes APC/C activity and anaphase in cells in culture. We show that CycB3 physically associates with the APC/C, is required for phosphorylation of APC3, and promotes APC/C association with its Cdc20 co-activators Fizzy and Cortex. Our results strongly suggest that CycB3-Cdk1 directly activates the APC/C to promote anaphase in both meiosis and mitosis.

CDC20 in and out of mitosis: a prognostic factor and therapeutic target in hematological malignancies

“…The association and the activity of the APC/C CDC20 complex is finely regulated. In addition to CDK1 and other mitotic kinases [ 71 , 72 ], Tank Binding Kinase 1 (TBK1) [ 73 ], CCNB3 [ 74 ], Apc1 loop domain (Apc1-loop 500 ) [ 75 ] and Hematopoietic PBX-interacting protein (HPIP) [ 76 ] were also shown to be involved. APC/C CDC20 exerts its function during the metaphase to anaphase transition ensuring proper chromatids segregation [ 35 ] (Fig.…”

Mitotic progression and dual spindle formation caused by spindle association of de novo–formed microtubule-organizing centers in parthenogenetic embryos of Drosophila ananassae

“…Mutations in D . melanogaster Cyclin B3 ( Yuan and O’Farrell 2015 ; Garrido et al 2020 ) and Elys ( Hirai et al 2018 ) exhibit maternal-effect lethality during a metaphase-like state of the first mitosis, accompanied by an anastral spindle that results from centrosome detachment from the spindle poles. Moreover, in fertilized eggs that are defective in pronuclear migration, an anastral spindle is assembled around replicated chromosomes of the female pronucleus, at a distance from the male pronucleus, where mitotic progression is halted in a metaphase-like state ( Llamazares et al 1999 ; Gergely et al 2000 ; Riparbelli et al 2000 ; Dix and Raff 2007 ; Varmark et al 2007 ; Vazquez-Pianzola et al 2022 ).…”

Mitotic checkpoint regulator RAE1 promotes tumor growth in colorectal cancer

“…To investigate whether RAE1 could be a therapeutic target, we performed a comprehensive analysis of 276 genes encoding microtubule‐regulating proteins 19 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 using TCGA data and evaluated their potential efficacy as a therapeutic target. We calculated the fold change in mRNA expression of each gene in tumor tissues compared to normal tissues, the correlation between mRNA expression and DNA copy number, and whether the high expression group was associated with poor prognosis.…”