Metaphase Kinetochores Research Articles

CKAP5 stabilizes CENP-E at kinetochores by regulating microtubule-chromosome attachments

Stabilization of microtubule plus end-directed kinesin CENP-E at the metaphase kinetochores is important for chromosome alignment, but its mechanism remains unclear. Here, we show that CKAP5, a conserved microtubule plus tip protein, regulates CENP-E at kinetochores in human cells. Depletion of CKAP5 impairs CENP-E localization at kinetochores at the metaphase plate and results in increased kinetochore–microtubule stability and attachment errors. Erroneous attachments are also supported by computational modeling. Analysis of CKAP5 knockout cancer cells of multiple tissue origins shows that CKAP5 is preferentially essential in aneuploid, chromosomally unstable cells, and the sensitivity to CKAP5 depletion is correlated to that of CENP-E depletion. CKAP5 depletion leads to reduction in CENP-E-BubR1 interaction and the interaction is rescued by TOG4-TOG5 domain of CKAP5. The same domain can rescue CKAP5 depletion-induced CENP-E removal from the kinetochores. Interestingly, CKAP5 depletion facilitates recruitment of PP1 to the kinetochores and furthermore, a PP1 target site-specific CENP-E phospho-mimicking mutant gets stabilized at kinetochores in the CKAP5-depleted cells. Together, the results support a model in which CKAP5 controls mitotic chromosome attachment errors by stabilizing CENP-E at kinetochores and by regulating stability of the kinetochore-attached microtubules.

Aurora B kinase erases monopolar microtubule-kinetochore arrays at the meiosis I-II transition

During meiosis, faithful chromosome segregation requires monopolar spindle microtubule-kinetochore arrays in MI to segregate homologous chromosomes, but bipolar in MII to segregate sister chromatids. Using fission yeasts, we found that the universal Aurora B kinase localizes to kinetochores in metaphase I and in the mid-spindle during anaphase I, as in mitosis; but in the absence of an intervening S phase, the importin α Imp1 propitiates its release from the spindle midzone to re-localize at kinetochores during meiotic interkinesis. We show that "error-correction" activity of kinetochore re-localized Aurora B becomes essential to erase monopolar arrangements from anaphase I, a prerequisite to satisfy the spindle assembly checkpoint (SAC) and to generate proper bipolar arrays at the onset of MII. This microtubule-kinetochore resetting activity of Aurora B at the MI-MII transition is required to prevent chromosome missegregation in meiosis II, a type of error often associated with birth defects and infertility in humans.

A bifunctional kinase-phosphatase module balances mitotic checkpoint strength and kinetochore-microtubule attachment stability.

Two major mechanisms safeguard genome stability during mitosis: the mitotic checkpoint delays mitosis until all chromosomes have attached to microtubules, and the kinetochore-microtubule error-correction pathway keeps this attachment process free from errors. We demonstrate here that the optimal strength and dynamics of these processes are set by a kinase-phosphatase pair (PLK1-PP2A) that engage in negative feedback from adjacent phospho-binding motifs on the BUB complex. Uncoupling this feedback to skew the balance towards PLK1 produces a strong checkpoint, hypostable microtubule attachments and mitotic delays. Conversely, skewing the balance towards PP2A causes a weak checkpoint, hyperstable microtubule attachments and chromosome segregation errors. These phenotypes are associated with altered BUB complex recruitment to KNL1-MELT motifs, implicating PLK1-PP2A in controlling auto-amplification of MELT phosphorylation. In support, KNL1-BUB disassembly becomes contingent on PLK1 inhibition when KNL1 is engineered to contain excess MELT motifs. This elevates BUB-PLK1/PP2A complex levels on metaphase kinetochores, stabilises kinetochore-microtubule attachments, induces chromosome segregation defects and prevents KNL1-BUB disassembly at anaphase. Together, these data demonstrate how a bifunctional PLK1/PP2A module has evolved together with the MELT motifs to optimise BUB complex dynamics and ensure accurate chromosome segregation.

Low tension recruits the yeast Aurora B protein Ipl1 to centromeres in metaphase.

Accurate genome segregation in mitosis requires that all chromosomes are bioriented on the spindle. Cells monitor biorientation by sensing tension across sister centromeres. Chromosomes that are not bioriented have low centromere tension, which allows Aurora B (yeast Ipl1) to perform error correction that locally loosens kinetochore-microtubule attachments to allow detachment of microtubules and fresh attempts at achieving biorientation. However, it is not known whether low tension recruits Aurora B to centromeres or, alternatively, whether low tension directly activates Aurora B already localized at centromeres. In this work, we experimentally induced low tension in metaphase Saccharomyces cerevisiae yeast cells, then monitored Ipl1 localization. We find low tension recruits Ipl1 to centromeres. Furthermore, low tension-induced Ipl1 recruitment depended on Bub1, which is known to provide a binding site for Ipl1. In contrast, Top2, which can also recruit Ipl1 to centromeres, was not required. Our results demonstrate cells are sensitive to low tension at centromeres and respond by actively recruiting Ip1l for error correction.

Nanoscale structural organization and stoichiometry of the budding yeast kinetochore.

Proper chromosome segregation is crucial for cell division. In eukaryotes, this is achieved by the kinetochore, an evolutionarily conserved multiprotein complex that physically links the DNA to spindle microtubules and takes an active role in monitoring and correcting erroneous spindle-chromosome attachments. Our mechanistic understanding of these functions and how they ensure an error-free outcome of mitosis is still limited, partly because we lack a complete understanding of the kinetochore structure in the cell. In this study, we use single-molecule localization microscopy to visualize individual kinetochore complexes in situ in budding yeast. For major kinetochore proteins, we measured their abundance and position within the metaphase kinetochore. Based on this comprehensive dataset, we propose a quantitative model of the budding yeast kinetochore. While confirming many aspects of previous reports based on bulk imaging, our results present a unifying nanoscale model of the kinetochore in budding yeast.

Self-organization of kinetochore-fibers in human mitotic spindles.

During eukaryotic cell division, chromosomes are linked to microtubules (MTs) in the spindle by a macromolecular complex called the kinetochore. The bound kinetochore microtubules (KMTs) are crucial to ensuring accurate chromosome segregation. Recent reconstructions by electron tomography (Kiewisz et al., 2022) captured the positions and configurations of every MT in human mitotic spindles, revealing that roughly half the KMTs in these spindles do not reach the pole. Here, we investigate the processes that give rise to this distribution of KMTs using a combination of analysis of large-scale electron tomography, photoconversion experiments, quantitative polarized light microscopy, and biophysical modeling. Our results indicate that in metaphase, KMTs grow away from the kinetochores along well-defined trajectories, with the speed of the KMT minus ends continually decreasing as the minus ends approach the pole, implying that longer KMTs grow more slowly than shorter KMTs. The locations of KMT minus ends, and the turnover and movements of tubulin in KMTs, are consistent with models in which KMTs predominately nucleate de novo at kinetochores in metaphase and are inconsistent with substantial numbers of non-KMTs being recruited to the kinetochore in metaphase. Taken together, this work leads to a mathematical model of the self-organization of kinetochore-fibers in human mitotic spindles.

Functional midbody assembly in the absence of a central spindle.

Contractile ring constriction during cytokinesis is thought to compact central spindle microtubules to form the midbody, an antiparallel microtubule bundle at the intercellular bridge. In Caenorhabditis elegans, central spindle microtubule assembly requires targeting of the CLASP family protein CLS-2 to the kinetochores in metaphase and spindle midzone in anaphase. CLS-2 targeting is mediated by the CENP-F-like HCP-1/2, but their roles in cytokinesis and midbody assembly are not known. We found that although HCP-1 and HCP-2 mostly function cooperatively, HCP-1 plays a more primary role in promoting CLS-2-dependent central spindle microtubule assembly. HCP-1/2 codisrupted embryos did not form central spindles but completed cytokinesis and formed functional midbodies capable of supporting abscission. These central spindle-independent midbodies appeared to form via contractile ring constriction-driven bundling of astral microtubules at the furrow tip. This work suggests that, in the absence of a central spindle, astral microtubules can support midbody assembly and that midbody assembly is more predictive of successful cytokinesis than central spindle assembly.

Kinetochore life histories reveal an Aurora-B-dependent error correction mechanism in anaphase.

SummaryChromosome mis-segregation during mitosis leads to aneuploidy, which is a hallmark of cancer and linked to cancer genome evolution. Errors can manifest as “lagging chromosomes” in anaphase, although their mechanistic origins and likelihood of correction are incompletely understood. Here, we combine lattice light-sheet microscopy, endogenous protein labeling, and computational analysis to define the life history of >104 kinetochores. By defining the “laziness” of kinetochores in anaphase, we reveal that chromosomes are at a considerable risk of mis-segregation. We show that the majority of lazy kinetochores are corrected rapidly in anaphase by Aurora B; if uncorrected, they result in a higher rate of micronuclei formation. Quantitative analyses of the kinetochore life histories reveal a dynamic signature of metaphase kinetochore oscillations that forecasts their anaphase fate. We propose that in diploid human cells chromosome segregation is fundamentally error prone, with an additional layer of anaphase error correction required for stable karyotype propagation.

An Integrative Computational Approach Based on Expression Similarity Signatures to Identify Protein-Protein Interaction Networks in Female-Specific Cancers.

Breast, ovarian, and endometrial cancers have a major impact on mortality in women. These tumors share hormone-dependent mechanisms involved in female-specific cancers which support tumor growth in a different manner. Integrated computational approaches may allow us to better detect genomic similarities between these different female-specific cancers, helping us to deliver more sophisticated diagnosis and precise treatments. Recently, several initiatives of The Cancer Genome Atlas (TCGA) have encouraged integrated analyses of multiple cancers rather than individual tumors. These studies revealed common genetic alterations (driver genes) even in clinically distinct entities such as breast, ovarian, and endometrial cancers. In this study, we aimed to identify expression similarity signatures by extracting common genes among TCGA breast (BRCA), ovarian (OV), and uterine corpus endometrial carcinoma (UCEC) cohorts and infer co-regulatory protein–protein interaction networks that might have a relationship with the estrogen signaling pathway. Thus, we carried out an unsupervised principal component analysis (PCA)-based computational approach, using RNA sequencing data of 2,015 female cancer and 148 normal samples, in order to simultaneously capture the data heterogeneity of intertumors. Firstly, we identified tumor-associated genes from gene expression profiles. Secondly, we investigated the signaling pathways and co-regulatory protein–protein interaction networks underlying these three cancers by leveraging the Ingenuity Pathway Analysis software. In detail, we discovered 1,643 expression similarity signatures (638 downregulated and 1,005 upregulated genes, with respect to normal phenotype), denoted as tumor-associated genes. Through functional genomic analyses, we assessed that these genes were involved in the regulation of cell-cycle-dependent mechanisms, including metaphase kinetochore formation and estrogen-dependent S-phase entry. Furthermore, we generated putative co-regulatory protein–protein interaction networks, based on upstream regulators such as the ERBB2/HER2 gene. Moreover, we provided an ad-hoc bioinformatics workflow with a manageable list of intertumor expression similarity signatures for the three female-specific cancers. The expression similarity signatures identified in this study might uncover potential estrogen-dependent molecular mechanisms promoting carcinogenesis.

Mechanobiology of the Mitotic Spindle.

The mitotic spindle is a microtubule-based assembly that separates the chromosomes during cell division. As the spindle is basically a mechanical micro machine, the understanding of its functioning is constantly motivating the development of experimental approaches based on mechanical perturbations, which are complementary to and work together with the classical genetics and biochemistry methods. Recent data emerging from these approaches in combination with theoretical modeling led to novel ideas and significant revisions of the basic concepts in the field. In this Perspective, we discuss the advances inthe understanding of spindle mechanics, focusing on microtubule forces that control chromosome movements.

Abstract PO-069: Characterizing cell-to-cell heterogeneity and chromosome instability induced by USP22 deficiency in colorectal cancer

Abstract Chromosome instability (CIN) is an aberrant phenotype characterized by an increased rate of gains and losses of chromosomes. CIN is observed in most cancer types, including 85% of colorectal cancer (CRC) cases. Although CIN is a driver of tumor heterogeneity and associated with drug resistance and poor patient prognosis, the genetic defects underlying CIN remain poorly understood. Ubiquitin Specific Peptidase 22 (USP22) is a deubiquitinating enzyme that targets mono-ubiquitin on lysine 120 of histone H2B (H2Bub1). H2Bub1 is a dynamic post-translational modification that modulates chromatin compaction. Importantly, homozygous or heterozygous USP22 deletion is observed in 45% of CRC cases, suggesting this may be a pathogenic event promoting CRC progression. Accordingly, we sought to characterize the impact reduced USP22 expression has on CIN. To reduce USP22 expression in karyotypically stable CRC (HCT116) and immortalized fibroblast (hTERT) cell lines, we employed transient siRNA silencing and stable CRISPR-Cas9 knockout (KO) models. Single-cell quantitative image-based analyses were utilized to monitor CIN-associated phenotypes, including changes in nuclear areas, micronucleus formation and chromosome numbers. In HCT116, USP22 silencing induced CIN phenotypes and an increase in H2Bub1 abundance in mitotic chromosomes. Subsequent mechanistic studies determined that this is accompanied by an increase in the recruitment of the spindle assembly checkpoint kinase BUB1 at metaphase centromeres and an increased frequency of lagging chromosomes in anaphase. Collectively, these data suggest that reduced USP22 expression alters H2Bub1 regulation in mitosis, which impairs mitotic fidelity, thereby inducing CIN. In addition, to assess the relevance of reduced USP22 expression in a distinct cellular context, the impact of USP22 silencing was assessed in hTERT, revealing similar CIN phenotypes, including changes in nuclear area and chromosome numbers. To assess the long-term impact USP22 deletions have on CIN, novel homozygous and heterozygous USP22-KO HCT116 clones were generated and monitored for three months, which revealed dynamic CIN phenotypes and ongoing changes in chromosome complements relative to controls. Collectively, these data identify USP22 as a novel CIN gene and indicate that USP22 deletions in cancer may drive intra-tumor genetic heterogeneity and thereby promote oncogenesis. Citation Format: Lucile M. Jeusset, Zelda D. Lichtensztejn, Kirk J. McManus. Characterizing cell-to-cell heterogeneity and chromosome instability induced by USP22 deficiency in colorectal cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-069.

Meiotic CENP-C is a shepherd: bridging the space between the centromere and the kinetochore in time and space.

While many of the proteins involved in the mitotic centromere and kinetochore are conserved in meiosis, they often gain a novel function due to the unique needs of homolog segregation during meiosis I (MI). CENP-C is a critical component of the centromere for kinetochore assembly in mitosis. Recent work, however, has highlighted the unique features of meiotic CENP-C. Centromere establishment and stability require CENP-C loading at the centromere for CENP-A function. Pre-meiotic loading of proteins necessary for homolog recombination as well as cohesion also rely on CENP-C, as do the main scaffolding components of the kinetochore. Much of this work relies on new technologies that enable in vivo analysis of meiosis like never before. Here, we strive to highlight the unique role of this highly conserved centromere protein that loads on to centromeres prior to M-phase onset, but continues to perform critical functions through chromosome segregation. CENP-C is not merely a structural link between the centromere and the kinetochore, but also a functional one joining the processes of early prophase homolog synapsis to late metaphase kinetochore assembly and signaling.

Characterization of unconventional kinetochore kinases KKT10 and KKT19 in Trypanosoma brucei.

ABSTRACTThe kinetochore is a macromolecular protein complex that drives chromosome segregation in eukaryotes. Unlike most eukaryotes that have canonical kinetochore proteins, evolutionarily divergent kinetoplastids, such as Trypanosoma brucei, have unconventional kinetochore proteins. T. brucei also lacks a canonical spindle checkpoint system, and it therefore remains unknown how mitotic progression is regulated in this organism. Here, we characterized, in the procyclic form of T. brucei, two paralogous kinetochore proteins with a CLK-like kinase domain, KKT10 and KKT19, which localize at kinetochores in metaphase but disappear at the onset of anaphase. We found that these proteins are functionally redundant. Double knockdown of KKT10 and KKT19 led to a significant delay in the metaphase to anaphase transition. We also found that phosphorylation of two kinetochore proteins, KKT4 and KKT7, depended on KKT10 and KKT19 in vivo. Finally, we showed that the N-terminal part of KKT7 directly interacts with KKT10 and that kinetochore localization of KKT10 depends not only on KKT7 but also on the KKT8 complex. Our results reveal that kinetochore localization of KKT10 and KKT19 is tightly controlled to regulate the metaphase to anaphase transition in T. brucei.This article has an associated First Person interview with the first author of the paper.

Maternal obesity enhances oocyte chromosome abnormalities associated with aging.

Obesity is increasing globally, and maternal obesity has adverse effects on pregnancy outcomes and the long-term health of offspring. Maternal obesity has been associated with pregnancy failure through impaired oogenesis and embryogenesis. However, whether maternal obesity causes chromosome abnormalities in oocytes has remained unclear. Here we show that chromosome abnormalities are increased in the oocytes of obese mice fed a high-fat diet and identify weakened sister-chromatid cohesion as the likely cause. Numbers of full-grown follicles retrieved from obese mice were the same as controls and the efficiency of in vitro oocyte maturation remained high. However, chromosome abnormalities presenting in both metaphase-I and metaphase-II were elevated, most prominently the premature separation of sister chromatids. Weakened sister-chromatid cohesion in oocytes from obese mice was manifested both as the terminalization of chiasmata in metaphase-I and as increased separation of sister centromeres in metaphase II. Obesity-associated abnormalities were elevated in older mice implying that maternal obesity exacerbates the deterioration of cohesion seen with advancing age.

Metaphase Kinetochore Movements are Regulated by Kinesin-8 Motors and Microtubule Dynamic Instability

During metaphase, sister chromatids are connected to microtubules (MTs) extending from the opposite spindle poles via kinetochores, protein complexes on the chromosome. Kinetochores congress to the equatorial plane of the spindle and oscillate around it, with kinesin-8 motors restricting these movements. Yet, the physical mechanism underlying kinetochore movements is unclear. We show that kinetochore movements in the fission yeast Schizosaccharomyces pombe are regulated by kinesin-8-promoted MT catastrophe, force-induced rescue and MT dynamic instability [1]. A candidate screen showed that among the selected motors only kinesin-8 motors Klp5/Klp6 are required for kinetochore centering. Our theoretical model, which uses force-balance equations to calculate movements of kinetochores [2] and Langevin description of MT dynamic instability shows that kinesin-8 motors are required for kinetochore centering, whereas sensitivity of rescue to force is necessary for the generation of oscillations. We found that irregular kinetochore movements occur for a broader range of parameters than regular oscillations. Thus, our work provides an explanation for how regulation of MT dynamic instability contributes to kinetochore congression and the accompanying movements around the spindle center. [1] K. Vukušić, R. Buđa, A. Bosilj, A. Milas, N. Pavin, and I.M. Tolić. Microtubule sliding within the bridging fiber pushes kinetochore fibers apart to segregate chromosomes. Dev. Cell. 43: 11-23 (2017). [2] A.H. Klemm, A. Bosilj, M. Glunčić, N. Pavin, and I.M. Tolić. Metaphase kinetochore movements are regulated by kinesin-8 motors and microtubule dynamic instability. Mol. Biol. Cell. 29: 1332-1345 (2018).

LUBAC controls chromosome alignment by targeting CENP-E to attached kinetochores

Faithful chromosome segregation requires proper chromosome congression at prometaphase and dynamic maintenance of the aligned chromosomes at metaphase. Chromosome missegregation can result in aneuploidy, birth defects and cancer. The kinetochore-bound KMN network and the kinesin motor CENP-E are critical for kinetochore-microtubule attachment and chromosome stability. The linear ubiquitin chain assembly complex (LUBAC) attaches linear ubiquitin chains to substrates, with well-established roles in immune response. Here, we identify LUBAC as a key player of chromosome alignment during mitosis. LUBAC catalyzes linear ubiquitination of the kinetochore motor CENP-E, which is specifically required for the localization of CENP-E at attached kinetochores, but not unattached ones. KNL1 acts as a receptor of linear ubiquitin chains to anchor CENP-E at attached kinetochores in prometaphase and metaphase. Thus, linear ubiquitination promotes chromosome congression and dynamic chromosome alignment by coupling the dynamic kinetochore microtubule receptor CENP-E to the static one, the KMN network.

CDK phosphorylation of Xenopus laevis M18BP1 promotes its metaphase centromere localization.

Chromosome segregation requires the centromere, the site on chromosomes where kinetochores assemble in mitosis to attach chromosomes to the mitotic spindle. Centromere identity is defined epigenetically by the presence of nucleosomes containing the histone H3 variant CENP-A. New CENP-A nucleosome assembly occurs at the centromere every cell cycle during G1, but how CENP-A nucleosome assembly is spatially and temporally restricted remains poorly understood. Centromere recruitment of factors required for CENP-A assembly is mediated in part by the three-protein Mis18 complex (Mis18α, Mis18β, M18BP1). Here, we show that Xenopus M18BP1 localizes to centromeres during metaphase-prior to CENP-A assembly-by binding to CENP-C using a highly conserved SANTA domain. We find that Cdk phosphorylation of M18BP1 is necessary for M18BP1 to bind CENP-C and localize to centromeres in metaphase. Surprisingly, mutations which disrupt the metaphase M18BP1/CENP-C interaction cause defective nuclear localization of M18BP1 in interphase, resulting in defective CENP-A nucleosome assembly. We propose that M18BP1 may identify centromeric sites in metaphase for subsequent CENP-A nucleosome assembly in interphase.

Histone methyltransferase SETD2 is required for meiotic maturation in mouse oocyte.

SET-domain-containing 2 (SETD2), a member of the histone lysine methyltransferase family, has been reported to be involved in multiple biological processes. However, the function of SETD2 during oocyte maturation has not been addressed. In this study, we find that mouse oocytes are incapable of progressing through meiosis completely once SETD2 is specifically depleted. These oocytes present an abnormal spindle morphology and deficient chromosome movement, with disrupted kinetochore-microtubule attachments, consequently producing aneuploidy eggs. In line with this, the BubR1 signal is markedly elevated in metaphase kinetochores of oocytes with SETD2 depletion, indicative of the activation of spindle assembly checkpoint. In addition, we note that loss of SETD2 results in a drastic decrease in the trimethylation level of H3K36 in oocytes. Collectively, our data demonstrate that SETD2 is required for oocyte maturation and indicate a novel mechanism controlling the meiotic apparatus.

Metaphase kinetochore movements are regulated by kinesin-8 motors and microtubule dynamic instability.

During metaphase, sister chromatids are connected to microtubules extending from the opposite spindle poles via kinetochores to protein complexes on the chromosome. Kinetochores congress to the equatorial plane of the spindle and oscillate around it, with kinesin-8 motors restricting these movements. Yet, the physical mechanism underlying kinetochore movements is unclear. We show that kinetochore movements in the fission yeast Schizosaccharomyces pombe are regulated by kinesin-8-promoted microtubule catastrophe, force-induced rescue, and microtubule dynamic instability. A candidate screen showed that among the selected motors only kinesin-8 motors Klp5/Klp6 are required for kinetochore centering. Kinesin-8 accumulates at the end of microtubules, where it promotes catastrophe. Laser ablation of the spindle resulted in kinetochore movement toward the intact spindle pole in wild-type and klp5Δ cells, suggesting that kinetochore movement is driven by pulling forces. Our theoretical model with Langevin description of microtubule dynamic instability shows that kinesin-8 motors are required for kinetochore centering, whereas sensitivity of rescue to force is necessary for the generation of oscillations. We found that irregular kinetochore movements occur for a broader range of parameters than regular oscillations. Thus, our work provides an explanation for how regulation of microtubule dynamic instability contributes to kinetochore congression and the accompanying movements around the spindle center.

TH2A is phosphorylated at meiotic centromere by Haspin.

Histone phosphorylation is sometimes associated with mitosis and meiosis. We have recently identified a phosphorylation of the 127th threonine on TH2A (pTH2A), a germ cell-specific H2A variant, in condensed spermatids and mitotic early preimplantation embryos of mice. Here, we further report the existence of pTH2A at the centromeres in metaphase I spermatocytes and oocytes. Moreover, we identified Haspin, a known kinase for the 3rd threonine on H3, is responsible for pTH2A in vivo. In contrast to the severe meiotic defect in oocytes treated with a Haspin inhibitor, pTH2A-deficient mice, in which the 127th threonine was replaced by alanine, maintained the fertility and exhibited no obvious defect in both oocytes and spermatogenesis. Interestingly, pTH2A was significantly decreased in aged oocytes, suggesting that its accumulation is regulated by centromeric cohesins. Collectively, our study proposes a new set of kinase-histone pair at meiotic centromere, which is highly coordinated during meiosis.