The Bub1-TPR Domain Interacts Directly with Mad3 to Generate Robust Spindle Checkpoint Arrest

Leontiou, Ioanna; London, Nitobe; May, Karen; Ma, Yingrui; Grzesiak, Lucile; Medina‐Pritchard, Bethan; Amin, Priya; Jeyaprakash, A. Arockia; Biggins, Sue; Hardwick, Kevin

doi:10.1016/j.cub.2019.06.011

Cited by 19 publications

(41 citation statements)

References 52 publications

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“…Therefore, we dimerized Mps1 with a Bub1 mutant wherein all 15 phosphorylation sites (T485, T486, T487, T488, T509, T518, S537, S539, S540, T541, T555, T556, T558, T566 and S578) within the central domain were rendered non-phosphorylatable. The eSAC activity was abolished in this case (Figure 1C bottom) [3, 16]. Consistently, this Bub1 mutant did not activate the SAC upon nocodazole treatment (Figure S1F, flow cytometry right panel).…”

Section: Resultssupporting

confidence: 57%

“…As expected, we observed a prolonged mitotic arrest (Figure 1C, also see Figure S1C left). The Mps1-Bub1 dimerization did not result in a cell cycle arrest when Mad2 was deleted, confirming that the arrest was mediated by ectopic SAC activation [13, 16]. Bub1 contributes two different activities to MCC formation (see schematic at the top of Figure 1C).…”

Section: Resultsmentioning

confidence: 63%

“…To circumvent these challenges, we used the ectopic SAC activation system, or eSAC. We and others have previously shown that the conditional dimerization of just the kinase domain of Mps1 with either a cytoplasmic fragment of Spc105/KNL1 containing repeating ‘MELT’ motifs or with Bub1 ultimately results in a kinetochore-independent activation of the SAC signaling cascade [13-16]. This eSAC signaling produces the MCC and delays anaphase onset, and therefore, provides an ideal assay for detecting the roles of Aurora B kinase activity in promoting MCC production.…”

Section: Resultsmentioning

confidence: 99%

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Aurora B phosphorylates Bub1 to promote spindle assembly checkpoint signaling

Roy

Han

Fontan

et al. 2021

Preprint

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SummaryAccurate chromosome segregation during cell division requires amphitelic attachment of each chromosome to the spindle apparatus. This is ensured by the Spindle Assembly Checkpoint (SAC) [1], which delays anaphase onset in response to unattached chromosomes, and an error correction mechanism, which eliminates syntelic chromosome attachments [2]. The SAC is activated by the Mps1 kinase. Mps1 sequentially phosphorylates the kinetochore protein Spc105/KNL1 to license the recruitment of several signaling proteins including Bub1. These proteins produce the Mitotic Checkpoint Complex (MCC), which delays anaphase onset [3-8]. The error correction mechanism is regulated by the Aurora B kinase, which phosphorylates the microtubule-binding interface of the kinetochore. Aurora B is also known to promote SAC signaling indirectly [9-12]. Here we present evidence that Aurora B kinase activity directly promotes MCC production in budding yeast and human cells. Using the ectopic SAC activation (eSAC) system, we find that the conditional dimerization of Aurora B (or an Aurora B recruitment domain) with either Bub1 or Mad1, but not the ‘MELT’ motifs in Spc105/KNL1, leads to a SAC-mediated mitotic arrest [13-16]. Importantly, ectopic MCC production driven by Aurora B requires the ability of Bub1 to bind both Mad1 and Cdc20. These and other data show that Aurora B cooperates with Bub1 to promote MCC production only after Mps1 licenses Bub1 recruitment to the kinetochore. This direct involvement of Aurora B in SAC signaling is likely important for syntelically attached sister kinetochores that must delay anaphase onset in spite of reduced Mps1 activity due to their end-on microtubule attachment.

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Section: Resultssupporting

confidence: 57%

Section: Resultsmentioning

confidence: 63%

Section: Resultsmentioning

confidence: 99%

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Aurora B phosphorylates Bub1 to promote spindle assembly checkpoint signaling

Roy

Han

Fontan

et al. 2021

Preprint

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“…PPARG is a crucial nuclear receptor that is the target of glitazone compounds used to treat T2D, but also plays an important role in connective tissue function, especially bone osteoblast and smooth muscle formation [44], [45]. BUB1 protein has an important role in cell division (mitosis) as a checkpoint regulator, so this (and functions in cell death regulation) could lead to many effects on bone and joint tissues [46]. AKT2 is a kinase enzyme regulator involved in cell signals; its function is strongly linked to T2D due to its involvement with insulin signaling, but it also plays a well established role in regulating the activity of bone forming cells [47].…”

Section: Discussionmentioning

confidence: 99%

Network-Based Computational Approach to Identify Delineating Common Cell Pathways Influencing Type 2 Diabetes and Diseases of Bone and Joints

Moni

Islam

Rahman³

et al. 2020

IEEE Access

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Developing type 2 diabetes (T2D) can increase patient risk of developing other common diseases and exacerbate their severity, including diseases that affect bone and joints. Such comorbidity interactions are hard to study in detail by traditional endocrinological methods. Thus, we developed tissue transcript analytical approaches to identify common pathways through which these diseases can interact. We examined RNAseq and microarray transcript datasets from studies of T2D and chronic bone and joint diseases, namely rheumatoid arthritis (RA), osteoarthritis (OA), juvenile idiopathic arthritis (JIA) and low peak bone density, a key osteoporosis (OP) determinant. These datasets contained data from affected individuals and matched controls. Differentially expressed genes (DEGs) for each condition were compared with T2D DEG. Overlapping DEGs (i.e., those common to T2D and a bone or joint condition) were subjected to gene enrichment by pathway analyses and by gene ontology methods, and the results were evaluated by using SNP-disease linkage (dbGaP) and gene-disease association (OMIM) databases that indicate gene involvement in pathologies. By examining gene targets of transcription factors (TFs) and microRNA (miRNAs), we also constructed DEG-TF and DEG-miRNA interactions networks for analysis. We identified strong candidate genes in common pathways, notably including SYK, UCP3, ROR1, PPARG, BUB1, AKT2, ADCY2 and CCR5. The DEG-TF network and DEG-miRNA interactions network analyses revealed a number of TFs (GATA2, FOXC1, USF2, YY1, E2F1, JUN, RELA, CREB1, TFAP2A, NFB1) and miRNAs (mir-335-5p, mir-16-5p, mir-26b-5p, mir-124-3p, mir-218-5p, mir-98-5p, mir-29b-3p, mir-3135b, mir-29c-3p, mir-1-1) that can regulate the identified DEGs at the transcriptional and post-transcriptional levels. Thus this data-driven approach has enabled identification and validation of regulatory factors and cell pathways by which T2D may influence bone and joint conditions, which may suggest new ways to interfere with the pathogenic processes involved.INDEX TERMS T2 diabetes, network-based approach, joint diseases, bone diseases.

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“…Bub1 binds to the kinetochore in connection with the KNL1 Spc105/Spc7 kinetochore protein phosphorylated by Mps1 Mph1 and Bub3. Heterodimers of Mps1 Mph1 and Bub1 together with Mad1, Mad2 and Mad3 are sufficient to trigger metaphase arrest in both budding and fission yeast [14].…”

Section: Introductionmentioning

confidence: 99%

CaMad2 Promotes Multiple Aspects of Genome Stability Beyond Its Direct Function in Chromosome Segregation

Vossen

Alhosawi

Aney

et al. 2019

Genes

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Mad2 is a central component of the spindle assembly checkpoint required for accurate chromosome segregation. Additionally, in some organisms, Mad2 has roles in preventing mutations and recombination through the DNA damage response. In the fungal pathogen Candida albicans, CaMad2 has previously been shown to be required for accurate chromosome segregation, survival in high levels of hydrogen peroxide, and virulence in a mouse model of infection. In this work, we showed that CaMad2 promotes genome stability through its well-characterized role in promoting accurate chromosome segregation and through reducing smaller scale chromosome changes due to recombination and DNA damage repair. Deletion of MAD2 decreased cell growth, increased marker loss rates, increased sensitivity to microtubule-destabilizing drugs, and increased sensitivity to DNA damage inducing treatments. CaMad2-GFP localized to dots, consistent with a role in kinetochore binding, and to the nuclear periphery, consistent with an additional role in DNA damage. Furthermore, deletion of MAD2 increases growth on fluconazole, and fluconazole treatment elevates whole chromosome loss rates in the mad2∆/∆ strain, suggesting that CaMad2 may be important for preventing fluconazole resistance via aneuploidy.

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The Bub1-TPR Domain Interacts Directly with Mad3 to Generate Robust Spindle Checkpoint Arrest

Cited by 19 publications

References 52 publications

Aurora B phosphorylates Bub1 to promote spindle assembly checkpoint signaling

Aurora B phosphorylates Bub1 to promote spindle assembly checkpoint signaling

Network-Based Computational Approach to Identify Delineating Common Cell Pathways Influencing Type 2 Diabetes and Diseases of Bone and Joints

CaMad2 Promotes Multiple Aspects of Genome Stability Beyond Its Direct Function in Chromosome Segregation

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