The universal triggering event of eukaryotic chromosome segregation is cleavage of centromeric cohesin by separase. Prior to anaphase, most separase is kept inactive by association with securin. Protein phosphatase 2A (PP2A) constitutes another binding partner of human separase, but the functional relevance of this interaction has remained enigmatic. We demonstrate that PP2A stabilizes separase-associated securin by dephosphorylation, while phosphorylation of free securin enhances its polyubiquitylation by the ubiquitin ligase APC/C and proteasomal degradation. Changing PP2A substrate phosphorylation sites to alanines slows degradation of free securin, delays separase activation, lengthens early anaphase, and results in anaphase bridges and DNA damage. In contrast, separase-associated securin is destabilized by introduction of phosphorylation-mimetic aspartates or extinction of separase-associated PP2A activity. G2- or prometaphase-arrested cells suffer from unscheduled activation of separase when endogenous securin is replaced by aspartate-mutant securin. Thus, PP2A-dependent stabilization of separase-associated securin prevents precocious activation of separase during checkpoint-mediated arrests with basal APC/C activity and increases the abruptness and fidelity of sister chromatid separation in anaphase.
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http://dx.doi.org/10.1002/embj.201488098 | DOI Listing |
Medicine (Baltimore)
September 2022
Department of Medical Humanities and Education Department, the First Affiliated Hospital, University of South China, Hengyang, China.
Background: Numerous studies have investigated the clinical significance of securin expression in solid cancers; however, the results have been inconsistent. Hence, we performed a meta-analysis of published studies to assess the clinical value of securin expression in patients with solid cancers.
Methods: The Chinese National Knowledge Infrastructure, Web of Science, PubMed, and EMDASE databases were searched for eligible studies (from inception up to April 2021).
Int J Mol Sci
April 2022
Health and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide 5000, Australia.
The accurate segregation of sister chromatids is complex, and errors that arise throughout this process can drive chromosomal instability and tumorigenesis. We recently showed that methylglyoxal (MGO), a glycolytic by-product, can cause chromosome missegregation events in lymphocytes. However, the underlying mechanisms of this were not explored.
View Article and Find Full Text PDFAdv Ther
June 2021
Department of Urology, The First Hospital of Qinhuangdao, No. 258 of Cultural North Road, Haigang District, Qinhuangdao, 066000, China.
Introduction: Metastatic prostate cancer (mPCa) is responsible for most prostate cancer (PCa) deaths worldwide. The present study aims to explore the molecular differences between mPCa and PCa.
Methods: The authors downloaded GSE6752, GSE6919, and GSE32269 from the Gene Expression Omnibus and employed integrated analysis to identify differentially expressed genes (DEGs) between mPCa and PCa.
Int J Med Sci
August 2021
PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan.
Breast cancer is the most common cancer type in females, and exploring the mechanisms of disease progression is playing a crucial role in the development of potential therapeutics. Pituitary tumor-transforming gene (PTTG) family members are well documented to be involved in cell-cycle regulation and mitosis, and contribute to cancer development by their involvement in cellular transformation in several tumor types. The critical roles of PTTG family members as crucial transcription factors in diverse types of cancers are recognized, but how they regulate breast cancer development still remains mostly unknown.
View Article and Find Full Text PDFNat Commun
November 2019
Department of Physiology, University of California, San Francisco, CA, 94143, USA.
Chromosome segregation begins when the cysteine protease, separase, cleaves the Scc1 subunit of cohesin at the metaphase-to-anaphase transition. Separase is inhibited prior to metaphase by the tightly bound securin protein, which contains a pseudosubstrate motif that blocks the separase active site. To investigate separase substrate specificity and regulation, here we develop a system for producing recombinant, securin-free human separase.
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