Dual recognition of chromatin and microtubules by INCENP is important for mitotic progression

Wheelock, Michael; Wynne, David J.; Tseng, Boo Shan

doi:10.1083/jcb.201609061

Cited by 41 publications

(64 citation statements)

References 96 publications

(144 reference statements)

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“…2m). Interestingly, these exchange dynamics are similar to what has been measured for INCENP at the inner centromeres in vivo (t 1/2 = 83.2 ± 33.5 s, ~55-60% mobile fraction) 27 . We also compared the diffusion rates of CPC components inside coacervates in vitro and at inner centromeres using fluorescence correlation spectroscopy (FCS).…”

Section: Resultssupporting

confidence: 83%

The inner centromere is a biomolecular condensate scaffolded by the chromosomal passenger complex

et al. 2019

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The inner centromere is a biomolecular condensate scaffolded by the chromosomal passenger complex.The inner centromere is a region on every mitotic chromosome that enables specific biochemical reactions that underlie properties, such as the maintenance of cohesion, the regulation of kinetochores and the assembly of specialized chromatin, that can resist microtubule pulling forces. The chromosomal passenger complex (CPC) is abundantly localized to the inner centromeres and it is unclear whether it is involved in non-kinase activities that contribute to the generation of these unique chromatin properties. We find that the borealin subunit of the CPC drives phase separation of the CPC in vitro at concentrations that are below those found on the inner centromere. We also provide strong evidence that the CPC exists in a phase-separated state at the inner centromere. CPC phase separation is required for its inner-centromere localization and function during mitosis. We suggest that the CPC combines phase separation, kinase and histone code-reading activities to enable the formation of a chromatin body with unique biochemical activities at the inner centromere.

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Section: Resultssupporting

confidence: 83%

The inner centromere is a biomolecular condensate scaffolded by the chromosomal passenger complex

et al. 2019

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“…Furthermore, our results may explain why cancer cells are more susceptible to CPC knockdown than to Aurora B inhibition (Ditchfield et al, 2003) and why artificial targeting of CEN-deleted INCENP to centromeres does not rescue CPC function (E. Wang et al, 2011; Wheelock et al, 2017). By ultimately controlling kinetochore assembly, error detection and correction, the CPC is a master regulator of kinetochore function.…”

Section: Discussionmentioning

confidence: 88%

Distinct Roles of the Chromosomal Passenger Complex in the Detection of and Response to Errors in Kinetochore-Microtubule Attachment

et al. 2017

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Summary The Chromosomal Passenger Complex (CPC) localizes to centromeres in early mitosis to activate its subunit Aurora B kinase. However, it is unclear if centromeric CPC localization contributes to CPC functions beyond Aurora B activation. Here, we show that an activated CPC that cannot localize to centromeres supports functional assembly of the outer kinetochore, but is unable to correct errors in kinetochore-microtubule attachment in Xenopus egg extracts. We find that CPC has two distinct roles at centromeres: one to properly phosphorylate Ndc80 to regulate attachment, and a second, conserved kinase-independent role in the proper composition of inner kinetochore proteins. Although a fully assembled inner kinetochore is not required for outer kinetochore assembly, we find it is essential to recruit tension indicators, such as BubR1 and 3F3/2, to erroneous attachments. Thus, centromeric CPC is necessary for tension-dependent removal of erroneous attachments, and for the kinetochore composition required to detect tension loss.

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“…Aurora B kinase is also required for the correction of erroneous kinetochore-microtubule attachments (Krenn and Musacchio, 2015). However, the exact roles of the central region in error correction are not fully understood (Vader et al, 2007;Fink et al, 2017;Fischböck-Halwachs et al, 2019;García-Rodríguez et al, 2019), likely due to the fact that the central region also regulates kinetochore assembly, the SAC, and microtubule assembly (current study; Tseng et al, 2010;Wheelock et al, 2017). Future efforts are required to identify additional kinetochore substrates that require high local concentrations of Aurora B.…”

Section: Discussionmentioning

confidence: 93%

Enrichment of Aurora B kinase at the inner kinetochore controls outer kinetochore assembly

Bonner

Haase

Swinderman

et al. 2019

Journal of Cell Biology

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Outer kinetochore assembly enables chromosome attachment to microtubules and spindle assembly checkpoint (SAC) signaling in mitosis. Aurora B kinase controls kinetochore assembly by phosphorylating the Mis12 complex (Mis12C) subunit Dsn1. Current models propose Dsn1 phosphorylation relieves autoinhibition, allowing Mis12C binding to inner kinetochore component CENP-C. Using Xenopus laevis egg extracts and biochemical reconstitution, we found that autoinhibition of the Mis12C by Dsn1 impedes its phosphorylation by Aurora B. Our data indicate that the INCENP central region increases Dsn1 phosphorylation by enriching Aurora B at inner kinetochores, close to CENP-C. Furthermore, centromere-bound CENP-C does not exchange in mitosis, and CENP-C binding to the Mis12C dramatically increases Dsn1 phosphorylation by Aurora B. We propose that the coincidence of Aurora B and CENP-C at inner kinetochores ensures the fidelity of kinetochore assembly. We also found that the central region is required for the SAC beyond its role in kinetochore assembly, suggesting that kinetochore enrichment of Aurora B promotes the phosphorylation of other kinetochore substrates.

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Dual recognition of chromatin and microtubules by INCENP is important for mitotic progression

Abstract: The chromosomal passenger complex contributes to the activation of the mitotic checkpoint and is composed of INCENP, Survivin, Borealin, and the kinase Aurora B. Wheelock et al. define the role of the INCENP domains binding chromatin and microtubules in the mitotic checkpoint.

Cited by 41 publications

References 96 publications

The inner centromere is a biomolecular condensate scaffolded by the chromosomal passenger complex

The inner centromere is a biomolecular condensate scaffolded by the chromosomal passenger complex

Distinct Roles of the Chromosomal Passenger Complex in the Detection of and Response to Errors in Kinetochore-Microtubule Attachment

Enrichment of Aurora B kinase at the inner kinetochore controls outer kinetochore assembly

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