Arrayed BUB recruitment modules in the kinetochore scaffold KNL1 promote accurate chromosome segregation

Vleugel, Mathijs; Tromer, Eelco C.; Omerzu, Manja; Groenewold, Vincent; Nijenhuis, Wilco; Snel, Berend; Kops, Geert J. P. L.

doi:10.1083/jcb.201307016

Cited by 133 publications

(243 citation statements)

References 37 publications

(86 reference statements)

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“…Recent studies by Vleugel et al has provided remarkable insight into the complexity in recognition of these MELT motifs and have also shown that Mps1-mediated phosphorylation of SHT motif encompassed within the MELT repeat augments SAC proficiency. 23 Nonetheless, it is noteworthy that SHT phosphorylation by Mps1 requires prior phosphorylation on MELT motifs. 23 The redundancy and necessity of multiple motifs i.e how many MELT repeats or whether all the MELT repeats are involved in recruiting BUB1 and BUB3 still remains enigmatic.…”

Section: The Ndc80 Complexmentioning

confidence: 99%

“…23 Nonetheless, it is noteworthy that SHT phosphorylation by Mps1 requires prior phosphorylation on MELT motifs. 23 The redundancy and necessity of multiple motifs i.e how many MELT repeats or whether all the MELT repeats are involved in recruiting BUB1 and BUB3 still remains enigmatic. It has been speculated that since binding affinity of BUB1:BUB3 to an individual MELT P is very high, each MELT repeat can potentially recruit a BUB1:BUB3 complex and therefore multiple BUB1:BUB3 complexes can concurrently bind to multiple MELT P repeats at a given time.…”

Section: The Ndc80 Complexmentioning

confidence: 99%

“…It has been speculated that since binding affinity of BUB1:BUB3 to an individual MELT P is very high, each MELT repeat can potentially recruit a BUB1:BUB3 complex and therefore multiple BUB1:BUB3 complexes can concurrently bind to multiple MELT P repeats at a given time. 23,24,30 Variations in the level of phosphorylation of different active repeats is likely to function as a governing factor or may provide a subtle layer of regulation in controlling the strength of SAC response but this hypothesis needs to be substantiated experimentally. In addition, the MELT repeats function cooperatively with the 2 N-terminally located, 10-12 amino acids long, and closely related yet distinct KI (LysIle) motifs, KI1 (KIDTTSFLANLK) and KI2 (KIDFNDFIKRLK) to directly recruit BUB1 and BUBR1, respectively, by binding to their tetratricopeptide repeat (TPR) domains to ensure robust SAC activity (Fig.…”

Section: The Ndc80 Complexmentioning

confidence: 99%

“…11,16,23 Loss of activity in the repeats is attributed to either degeneration or vast variation from the consensus in the 3 most important motifs, MELT, TV (V D aromatic amino acid) and SHT (located C-terminal of MELT). Recent studies by Vleugel et al has provided remarkable insight into the complexity in recognition of these MELT motifs and have also shown that Mps1-mediated phosphorylation of SHT motif encompassed within the MELT repeat augments SAC proficiency.…”

Section: The Ndc80 Complexmentioning

confidence: 99%

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How the SAC gets the axe: Integrating kinetochore microtubule attachments with spindle assembly checkpoint signaling

Agarwal

Varma

2015

BioArchitecture

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ABSTRACT. Mitosis entails the bona fide segregation of duplicated chromosomes. This process is accomplished by the attachment of kinetochores on chromosomes to microtubules (MTs) of the mitotic spindle. Once the appropriate attachment is achieved, the spindle assembly checkpoint (SAC) that delays the premature onset of anaphase needs to be silenced for the cell to proceed to anaphase and cytokinesis. Therefore, while it is imperative to preserve the SAC when kinetochores are unattached, it is of paramount importance that SAC components are removed post kinetochore microtubule (kMT) attachment. Precise knowledge of how kMT attachments trigger the removal of SAC components from kinetochores or how the checkpoint proteins feedback in to the attachment machinery remains elusive. This review aims to describe the recent advances that provide an insight into the interplay of molecular events that coordinate and regulate the SAC activity in response to kMT attachment during cell division.

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Section: The Ndc80 Complexmentioning

confidence: 99%

Section: The Ndc80 Complexmentioning

confidence: 99%

Section: The Ndc80 Complexmentioning

confidence: 99%

Section: The Ndc80 Complexmentioning

confidence: 99%

See 2 more Smart Citations

How the SAC gets the axe: Integrating kinetochore microtubule attachments with spindle assembly checkpoint signaling

Agarwal

Varma

2015

BioArchitecture

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“…When phosphorylated, these motifs recruit BUB1-BUB3 dimers that are essential for SAC signaling and chromosome bi-orientation (Krenn et al, 2014;Primorac et al, 2013;Vleugel et al, 2013Vleugel et al, , 2015Zhang et al, 2014). Since the discovery of BUB1, the molecular mechanism by which it participates in SAC activation has been a matter of controversy.…”

Section: Introductionmentioning

confidence: 99%

Dissecting the roles of human BUB1 in the spindle assembly checkpoint

Vleugel

Hoek

Tromer

et al. 2015

Journal of Cell Science

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Mitotic chromosome segregation is initiated by the anaphase promoting complex/cyclosome (APC/C) and its co-activator CDC20 (forming APC/C CDC20 ). APC/C CDC20 is inhibited by the spindle assembly checkpoint (SAC) when chromosomes have not attached to spindle microtubules. Unattached kinetochores catalyze the formation of a diffusible APC/C CDC20 inhibitor that comprises BUBR1 (also known as BUB1B), BUB3, MAD2 (also known as MAD2L1) and a second molecule of CDC20. Recruitment of these proteins to the kinetochore, as well as SAC activation, rely on the mitotic kinase BUB1, but the molecular mechanism by which BUB1 accomplishes this in human cells is unknown. We show that kinetochore recruitment of BUBR1 and BUB3 by BUB1 is dispensable for SAC activation. Unlike its yeast and nematode orthologs, human BUB1 does not associate stably with the MAD2 activator MAD1 (also known as MAD1L1) and, although required for accelerating the loading of MAD1 onto kinetochores, BUB1 is dispensable for the maintenance of steady-state levels of MAD1 there. Instead, we identify a 50-amino-acid segment that harbors the recently reported ABBA motif close to a KEN box as being crucial for the role of BUB1 in SAC signaling. The presence of this segment correlates with SAC activity and efficient binding of CDC20 but not of MAD1 to kinetochores.

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From the Nuclear Pore to the Fibrous Corona: A MAD Journey to Preserve Genome Stability

Cunha-Silva

Conde

2020

BioEssays

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The relationship between kinetochores and nuclear pore complexes (NPCs) is intimate but poorly understood. Several NPC components and associated proteins are relocated to mitotic kinetochores to assist in different activities that ensure faithful chromosome segregation. Such is the case of the Mad1-c-Mad2 complex, the catalytic core of the spindle assembly checkpoint (SAC), a surveillance pathway that delays anaphase until all kinetochores are attached to spindle microtubules. Mad1-c-Mad2 is recruited to discrete domains of unattached kinetochores from where it promotes the rate-limiting step in the assembly of anaphase-inhibitory complexes. SAC proficiency further requires Mad1-c-Mad2 to be anchored at NPCs during interphase. However, the mechanistic relevance of this arrangement for SAC function remains ill-defined. Recent studies uncover the molecular underpinnings that coordinate the release of Mad1-c-Mad2 from NPCs with its prompt recruitment to kinetochores. Here, current knowledge on Mad1-c-Mad2 function and spatiotemporal regulation is reviewed and the critical questions that remain unanswered are highlighted.

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Arrayed BUB recruitment modules in the kinetochore scaffold KNL1 promote accurate chromosome segregation

Abstract: The kinetochore scaffold KNL1 contains an extensive array of short linear sequence modules that each independently can localize BUB1 but that together provide enhanced efficiency of chromosome segregation.

Cited by 133 publications

References 37 publications

How the SAC gets the axe: Integrating kinetochore microtubule attachments with spindle assembly checkpoint signaling

How the SAC gets the axe: Integrating kinetochore microtubule attachments with spindle assembly checkpoint signaling

Dissecting the roles of human BUB1 in the spindle assembly checkpoint

From the Nuclear Pore to the Fibrous Corona: A MAD Journey to Preserve Genome Stability

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