Two functionally distinct kinetochore pools of BubR1 ensure accurate chromosome segregation

Zhang, Gang; Méndez, Blanca López; Sedgwick, Garry G.; Nilsson, Jakob

doi:10.1038/ncomms12256

Cited by 42 publications

(57 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is clear that phosphorylation of Met-Glu-Leu-Thr (MELT) repeats in the outer kinetochore protein KNL1 by the checkpoint kinase Mps1 generates binding sites for the checkpoint complexes Bub1/Bub3 and BubR1/Bub3 (London et al, 2012;Shepperd et al, 2012;Yamagishi et al, 2012;Vleugel et al, 2013Vleugel et al, , 2015bZhang et al, 2014Zhang et al, , 2016. Answering this requires dissection of the molecular mechanisms of checkpoint protein recruitment to the kinetochore and of the interactions between checkpoint proteins.…”

Section: Introductionmentioning

confidence: 99%

“…Answering this requires dissection of the molecular mechanisms of checkpoint protein recruitment to the kinetochore and of the interactions between checkpoint proteins. It is clear that phosphorylation of Met-Glu-Leu-Thr (MELT) repeats in the outer kinetochore protein KNL1 by the checkpoint kinase Mps1 generates binding sites for the checkpoint complexes Bub1/Bub3 and BubR1/Bub3 (London et al, 2012;Shepperd et al, 2012;Yamagishi et al, 2012;Vleugel et al, 2013Vleugel et al, , 2015bZhang et al, 2014Zhang et al, , 2016. Subsequent phosphorylation of Bub1 by Mps1 then facilitates an interaction between Mad1 and Bub1 a mechanism conserved from yeast to man (London & Biggins, 2014;Mora-Santos et al, 2016;Faesen et al, 2017;Ji et al, 2017;Qian et al, 2017;Zhang et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Efficient mitotic checkpoint signaling depends on integrated activities of Bub1 and the RZZ complex

et al. 2019

Self Cite

View full text Add to dashboard Cite

Kinetochore localized Mad1 is essential for generating a “wait anaphase” signal during mitosis, hereby ensuring accurate chromosome segregation. Inconsistent models for the function and quantitative contribution of the two mammalian Mad1 kinetochore receptors: Bub1 and the Rod‐Zw10‐Zwilch (RZZ) complex exist. By combining genome editing and RNAi, we achieve penetrant removal of Bub1 and Rod in human cells, which reveals that efficient checkpoint signaling depends on the integrated activities of these proteins. Rod removal reduces the proximity of Bub1 and Mad1, and we can bypass the requirement for Rod by tethering Mad1 to kinetochores or increasing the strength of the Bub1‐Mad1 interaction. We find that Bub1 has checkpoint functions independent of Mad1 localization that are supported by low levels of Bub1 suggesting a catalytic function. In conclusion, our results support an integrated model for the Mad1 receptors in which the primary role of RZZ is to localize Mad1 at kinetochores to generate the Mad1‐Bub1 complex.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Efficient mitotic checkpoint signaling depends on integrated activities of Bub1 and the RZZ complex

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…4 and supplemental Fig. S3) (6,(36)(37)(38). These SAC complexes are critical to the establishment and maintenance of the SAC (39) and their identification was an indication that our proximity-based labeling approach was robust.…”

Section: Analysis Of the Core Sac Protein Proximity Association Netwomentioning

confidence: 97%

Dissection of the Spindle Assembly Checkpoint by Proximity Proteomics

Garcia

Velasquez

Gao

et al. 2020

Preprint

View full text Add to dashboard Cite

The spindle assembly checkpoint (SAC) is critical for sensing defective microtubule-kinetochore attachments and tension across the kinetochore and functions to arrest cells in prometaphase to allow time to repair any errors prior to proceeding into anaphase. The SAC has a central role in ensuring the fidelity of chromosome segregation and its dysregulation has been linked to the development of human diseases like cancer. The establishment and maintenance of the SAC relies on multiple protein complexes that are intricately regulated in a spatial and temporal manner through posttranslational modifications like phosphorylation. Over the past few decades the SAC has been highly investigated and much has been learned about its protein constituents and the pathways and factors that regulate its activity. However, the spatio-temporal proximity associations of the core SAC components have not been explored in a systematic manner. Here, we have taken a BioID2 proximity-labeling proteomic approach to define the proximity protein environment for each of the five core SAC proteins BUB1, BUB3, BUBR1, MAD1L1, and MAD2L1 under conditions where the SAC is active in prometaphase. These five protein association maps were integrated to generate the SAC proximity protein network that contains multiple layers of information related to core SAC protein complexes, protein-protein interactions, and proximity associations. Our analysis validated many of the known SAC complexes and protein-protein interactions. Additionally, it uncovered new protein associations that lend insight into the functioning of the SAC and highlighted future areas that should be investigated to generate a comprehensive understanding of the SAC.3

show abstract

“…Among other 18 functions, PLK1 directly binds and phosphorylates BUBR1 at several residues including the 19 attachment-sensitive site S670 18 and the two tension-sensitive sites S676 19 and T680 20 in 20 prometaphase allowing the formation of stable kinetochore-microtubule attachments. This 21 activity needs to be tightly regulated to ensure proper alignment of the chromosomes at the 22 metaphase plate 8,9,19 . The kinase activity of Aurora B is an essential to destabilize erroneous 23 kinetochore-microtubule interactions 21 whereas the phosphatase PP2A protects initial 24 kinetochore-microtubule interactions from excessive destabilization by Aurora B 22 .…”

mentioning

confidence: 99%

“…BRCA2 has also emerging functions in mitosis, for example, at the kinetochore, it forms a 6 complex with BUBR1 4,5 , an essential factor for the faithful segregation of chromosomes that 7 is required for kinetochore-microtubule attachment and is a component of the spindle 8 assembly checkpoint (SAC) 6,7 . These two activities of BUBR1 involve different partners and 9 are functionally distinct 8,9 . BRCA2 has been proposed to contribute to BUBR1 SAC activity 10 through direct binding and promoting its acetylation by the acetyl transferase PCAF 4,10 , 11 although due to confounding results in the BUBR1 interaction site in BRCA2, it is unclear if 12 this interaction is direct 4,5 .…”

mentioning

confidence: 99%

Proper chromosome alignment depends on BRCA2 phosphorylation by PLK1

Ehlén

Martin

Julien

et al. 2018

Preprint

View full text Add to dashboard Cite

SummaryThe BRCA2 tumor suppressor protein is involved in the maintenance of genome integrity through its role in homologous recombination. In mitosis, BRCA2 is phosphorylated by Polo-like kinase 1 (PLK1). Here we describe how this phosphorylation contributes to the control of mitosis. We identified two highly conserved phosphorylation sites at S193 and T207 of BRCA2. Phosphorylated-T207 is a bona fide docking site for PLK1 as illustrated by the crystal structure of the BRCA2 peptide bound to PLK1 Polo-box domain. We found that BRCA2 bound to PLK1 forms a complex with the phosphatase PP2A and phosphorylated-BUBR1. Reducing BRCA2 binding to PLK1, as observed in BRCA2 breast cancer variants S206C and T207A, alters the tetrameric complex resulting in misaligned chromosomes, faulty chromosome segregation and aneuploidy. We thus reveal a direct role of BRCA2 in the alignment of chromosomes, distinct from its DNA repair function, with important consequences on chromosome stability. These findings may explain in part the aneuploidy observed in BRCA2-mutated tumors.

show abstract

Two functionally distinct kinetochore pools of BubR1 ensure accurate chromosome segregation

Cited by 42 publications

References 41 publications

Efficient mitotic checkpoint signaling depends on integrated activities of Bub1 and the RZZ complex

Efficient mitotic checkpoint signaling depends on integrated activities of Bub1 and the RZZ complex

Dissection of the Spindle Assembly Checkpoint by Proximity Proteomics

Proper chromosome alignment depends on BRCA2 phosphorylation by PLK1

Contact Info

Product

Resources

About