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Redox priming promotes Aurora A activation during mitosis.

ABSTRACT: Cell cycle-dependent redox changes can mediate transient covalent modifications of cysteine thiols to modulate the activities of regulatory kinases and phosphatases. Our previously reported finding that protein cysteine oxidation is increased during mitosis relative to other cell cycle phases suggests that redox modifications could play prominent roles in regulating mitotic processes. The Aurora family of kinases and their downstream targets are key components of the cellular machinery that ensures the proper execution of mitosis and the accurate segregation of chromosomes to daughter cells. In this study, x-ray crystal structures of the Aurora A kinase domain delineate redox-sensitive cysteine residues that, upon covalent modification, can allosterically regulate kinase activity and oligomerization state. We showed in both Xenopus laevis egg extracts and mammalian cells that a conserved cysteine residue within the Aurora A activation loop is crucial for Aurora A activation by autophosphorylation. We further showed that covalent disulfide adducts of this residue promote autophosphorylation of the Aurora A kinase domain. These findings reveal a potential mechanistic link between Aurora A activation and changes in the intracellular redox state during mitosis and provide insights into how novel small-molecule inhibitors may be developed to target specific subpopulations of Aurora A.

SUBMITTER: Lim DC

PROVIDER: S-EPMC8514121 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Redox priming promotes Aurora A activation during mitosis

Project description:Samples of Aurora A kinase domain were covalently labeled with disulfide-containing compounds and analyzed by mass spectrometry to determine the extent of covalent labeling.

2020-06-28 | MSV000085641 | MassIVE

Aurora A activation in mitosis promoted by BuGZ.

Project description:Protein phase separation or coacervation has emerged as a potential mechanism to regulate biological functions. We have shown that coacervation of a mostly unstructured protein, BuGZ, promotes assembly of spindle and its matrix. BuGZ in the spindle matrix binds and concentrates tubulin to promote microtubule (MT) assembly. It remains unclear, however, whether BuGZ could regulate additional proteins to promote spindle assembly. In this study, we report that BuGZ promotes Aurora A (AurA) activation in vitro. Depletion of BuGZ in cells reduces the amount of phosphorylated AurA on spindle MTs. BuGZ also enhances MCAK phosphorylation. The two zinc fingers in BuGZ directly bind to the kinase domain of AurA, which allows AurA to incorporate into the coacervates formed by BuGZ in vitro. Importantly, mutant BuGZ that disrupts the coacervation activity in vitro fails to promote AurA phosphorylation in Xenopus laevis egg extracts. These results suggest that BuGZ coacervation promotes AurA activation in mitosis.

| S-EPMC5748987 | biostudies-literature

Aurora-A regulates MCRS1 function during mitosis.

Project description:The mitotic spindle is made of microtubules (MTs) nucleated through different pathways involving the centrosomes, the chromosomes or the walls of pre-existing MTs. MCRS1 is a RanGTP target that specifically associates with the chromosome-driven MTs protecting them from MT depolymerases. MCRS1 is also needed for the control of kinetochore fiber (K-fiber) MT minus-ends dynamics in metaphase. Here, we investigated the regulation of MCRS1 activity in M-phase. We show that MCRS1 is phosphorylated by the Aurora-A kinase in mitosis on Ser35/36. Although this phosphorylation has no role on MCRS1 localization to chromosomal MTs and K-fiber minus-ends, we show that it regulates MCRS1 activity in mitosis. We conclude that Aurora-A activity is particularly important in the tuning of K-fiber minus-ends dynamics in mitosis.

| S-EPMC4957591 | biostudies-literature

RNA stimulates Aurora B kinase activity during mitosis.

Project description:Accurate chromosome segregation is essential for cell viability. The mitotic spindle is crucial for chromosome segregation, but much remains unknown about factors that regulate spindle assembly. Recent work implicates RNA in promoting proper spindle assembly independently of mRNA translation; however, the mechanism by which RNA performs this function is currently unknown. Here, we show that RNA regulates both the localization and catalytic activity of the mitotic kinase, Aurora-B (AurB), which is present in a ribonucleoprotein (RNP) complex with many mRNAs. Interestingly, AurB kinase activity is reduced in Xenopus egg extracts treated with RNase, and its activity is stimulated in vitro by RNA binding. Spindle assembly defects following RNase-treatment are partially rescued by inhibiting MCAK, a microtubule depolymerase that is inactivated by AurB-dependent phosphorylation. These findings implicate AurB as an important RNA-dependent spindle assembly factor, and demonstrate a translation-independent role for RNA in stimulating AurB.

| S-EPMC4072698 | biostudies-literature

Functional interaction of Aurora-A and PP2A during mitosis.

Project description:Entry into mitosis is a highly regulated process, promoted by the activated Cyclin B1/Cdk1 complex. Activation of this complex is controlled, in part, by the protein kinase Aurora-A, which is a member of a multigenic serine/threonine kinase family. In normal cells, Aurora-A activity is regulated, at least in part, by degradation through the APC-ubiquitin-proteasome pathway. It has recently been proposed that, in Xenopus, Aurora-A degradation can be inhibited by phosphorylation. It would thus be expected that a phosphatase activity would release this blockade at the end of mitosis. Here, we have shown that the protein phosphatase PP2A and Aurora-A are colocalized at the cell poles during mitosis in human cells and interact within the same complex. Using the PP2A inhibitor okadaic acid and an RNAi approach, we have shown that this interaction is functional within the cell. PP2A/Aurora-A interaction is promoted by an S51D mutation in Aurora-A and inhibited by a phosphomimetic peptide centered around Aurora-A S51, thereby strongly suggesting that PP2A controls Aurora-A degradation by dephosphorylating serine 51 in the A box of the human enzyme.

| S-EPMC1839003 | biostudies-literature

Aurora B kinase activation requires survivin priming phosphorylation by PLK1.

Project description:During cell division, chromosome segregation is orchestrated by the interaction of spindle microtubules with the centromere. Accurate attachment of spindle microtubules to kinetochore requires the chromosomal passenger of Aurora B kinase complex with borealin, INCENP and survivin (SUR). The current working model argues that SUR is responsible for docking Aurora B to the centromere whereas its precise role in Aurora B activation has been unclear. Here, we show that Aurora B kinase activation requires SUR priming phosphorylation at Ser20 which is catalyzed by polo-like kinase 1 (PLK1). Inhibition of PLK1 kinase activity or expression of non-phosphorylatable SUR mutant prevents Aurora B activation and correct spindle microtubule attachment. The PLK1-mediated regulation of Aurora B kinase activity was examined in real-time mitosis using fluorescence resonance energy transfer-based reporter and quantitative analysis of native Aurora B substrate phosphorylation. We reason that the PLK1-mediated priming phosphorylation is critical for orchestrating Aurora B activity in centromere which is essential for accurate chromosome segregation and faithful completion of cytokinesis.

| S-EPMC3150119 | biostudies-literature

Aurora A Phosphorylation of YY1 during Mitosis Inactivates its DNA Binding Activity.

Project description:Successful execution of mitotic cell division requires the tight synchronisation of numerous biochemical pathways. The underlying mechanisms that govern chromosome segregation have been thoroughly investigated. However, the mechanisms that regulate transcription factors in coordination with mitotic progression remain poorly understood. In this report, we identify the transcription factor YY1 as a novel mitotic substrate for the Aurora A kinase, a key regulator of critical mitotic events, like centrosome maturation and spindle formation. Using in vitro kinase assays, we show that Aurora A directly phosphorylates YY1 at serine 365 in the DNA-binding domain. Using a new phospho-specific antibody, we show that YY1 phosphorylation at serine 365 occurs during mitosis, and that this phosphorylation is significantly reduced upon inhibition of Aurora A. Furthermore, we show, using electrophoretic mobility shift and chromatin immunoprecipitation assays, that phosphorylation of YY1 at this site abolishes its DNA binding activity in vitro and in vivo. In conformity with this loss of binding activity, phosphorylated YY1 also loses its transctivation ability as demonstrated by a luciferase reporter assay. These results uncover a novel mechanism that implicates Aurora A in the mitotic inactivation of transcription factors.

| S-EPMC5577188 | biostudies-literature

Different roles for Aurora B in condensin targeting during mitosis and meiosis.

Project description:Condensin complexes are essential for mitotic and meiotic chromosome segregation. Caenorhabditis elegans, like other metazoans, has two distinct mitotic and meiotic condensin complexes (I and II), which occupy distinct chromosomal domains and perform non-redundant functions. Despite the differences in mitotic and meiotic chromosome behavior, we uncovered several conserved aspects of condensin targeting during these processes. During both mitosis and meiosis, condensin II loads onto chromosomes in early prophase, and condensin I loads at entry into prometaphase. During both mitosis and meiosis, the localization of condensin I, but not condensin II, closely parallels the localization of the chromosomal passenger kinase Aurora B (AIR-2 in C. elegans). Interestingly, condensin I and AIR-2 also colocalize on the spindle midzone during anaphase of mitosis, and between separating chromosomes during anaphase of meiosis. Consistently, AIR-2 affects the targeting of condensin I but not condensin II. However, the role AIR-2 plays in condensin I targeting during these processes is different. In mitosis, AIR-2 activity is required for chromosomal association of condensin I. By contrast, during meiosis, AIR-2 is not required for condensin I chromosomal association, but it provides cues for correct spatial targeting of the complex.

| S-EPMC3215577 | biostudies-literature

Human RASSF7 regulates the microtubule cytoskeleton and is required for spindle formation, Aurora B activation and chromosomal congression during mitosis.

Project description:RASSF7, a member of the N-terminal Ras association domain family, has increased expression in various cancers and, on the basis of our previous work in Xenopus embryos, may be a regulator of mitosis. In the present study, we address, for the first time, the role of human RASSF7 in mitosis. We demonstrate that RASSF7 is expressed in a broad range of different cell types and that this expression could be enhanced following exposure to hypoxia. Knocking down RASSF7 in human cell lines inhibited cell growth and induced defects in mitosis, including aberrant spindle formation and a failure in chromosomal congression. In order to understand the molecular basis of the defects in more detail, we analysed the activity of mitotic signalling proteins and found that activation of Aurora B did not occur in cells in which RASSF7 was knocked down. We also show that endogenous RASSF7 protein localizes to the centrosome and demonstrate using microtubule-regrowth assays that RASSF7 is an important regulator of microtubule dynamics. On the basis of these observations, we propose that, owing to its key role in regulating the microtubule cytoskeleton, RASSF7 is required for mitosis in human cells.

| S-EPMC2922839 | biostudies-literature

Untangling the contribution of Haspin and Bub1 to Aurora B function during mitosis.

Project description:Aurora B kinase is essential for faithful chromosome segregation during mitosis. During (pro)metaphase, Aurora B is concentrated at the inner centromere by the kinases Haspin and Bub1. However, how Haspin and Bub1 collaborate to control Aurora B activity at centromeres remains unclear. Here, we show that either Haspin or Bub1 activity is sufficient to recruit Aurora B to a distinct chromosomal locus. Moreover, we identified a small, Bub1 kinase-dependent Aurora B pool that supported faithful chromosome segregation in otherwise unchallenged cells. Joined inhibition of Haspin and Bub1 activities fully abolished Aurora B accumulation at centromeres. While this impaired the correction of erroneous KT-MT attachments, it did not compromise the mitotic checkpoint, nor the phosphorylation of the Aurora B kinetochore substrates Hec1, Dsn1, and Knl1. This suggests that Aurora B substrates at the kinetochore are not phosphorylated by centromere-localized pools of Aurora B, and calls for a reevaluation of the current spatial models for how tension affects Aurora B-dependent kinetochore phosphorylation.

| S-EPMC7054988 | biostudies-literature

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