Crowning the Kinetochore: The Fibrous Corona in Chromosome Segregation

Kops, Geert J.P.L.; Gassmann, Reto

doi:10.1016/j.tcb.2020.04.006

Cited by 58 publications

(82 citation statements)

References 91 publications

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“…One such situation is dividing cells containing kinetochores with end-on, but syntelic, attachments (Figure 4C). End-on attachments are sufficient to suppress Mps1 activity [48-51] and weaken Mad1 recruitment via the core SAC signaling cascade and possibly through the fibrous corona [52]. Despite the lowered Mps1 activity under this condition, Aurora B, which is enriched at these kinetochores, can promote MCC formation by phosphorylating Bub1, delay anaphase onset, and thereby reduce chromosome missegregation.…”

Section: Resultsmentioning

confidence: 99%

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: Resultsmentioning

confidence: 99%

Aurora B phosphorylates Bub1 to promote spindle assembly checkpoint signaling

Roy

Han

Fontan

et al. 2021

Preprint

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“…During metaphase, the SAC acts to ensure that each chromatid is stably attached to microtubules emanating from opposite poles before proceeding to anaphase. The kinetochore is the prime apparatus for spindle attachment, upon which sensors and effectors for SAC regulation assemble [56,57]. We have previously shown that the FA signaling pathway regulates SAC activity and that FAdeficient cells exhibit a weakened SAC (Fig S5) [5,4].…”

Section: Discussionmentioning

confidence: 99%

SIK2 kinase synthetic lethality is driven by spindle assembly defects in FANCA‐deficient cells

et al. 2021

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The Fanconi anemia (FA) pathway safeguards genomic stability through cell cycle regulation and DNA damage repair. The canonical tumor suppressive role of FA proteins in the repair of DNA damage during interphase is well established, but their function in mitosis is incompletely understood. Here we performed a kinome-wide synthetic lethality screen in FANCA-/-fibroblasts, which revealed multiple mitotic kinases as necessary for survival of FANCA-deficient cells. Among these kinases, we identified the depletion of the centrosome kinase SIK2 as synthetic lethal upon loss of FANCA. We found that FANCA co-localizes with SIK2 at multiple mitotic structures and regulates the activity of SIK2 at centrosomes. Furthermore, we found that loss of FANCA exacerbates cell cycle defects induced by pharmacological inhibition of SIK2, including impaired G2-M transition, delayed mitotic progression, and cytokinesis failure. In addition, we showed that inhibition of SIK2 abrogates nocodazole-induced prometaphase arrest, suggesting a novel role for SIK2 in the spindle assembly checkpoint. Together, these findings demonstrate that FANCA-deficient cells are dependent upon SIK2 for survival, supporting a preclinical rationale for targeting of SIK2 in FA-disrupted cancers.

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“…Based on functional analysis, Allan et al (2020) propose that the Mad1–cyclin B1 interaction is critical for recruitment of Mad1–Mad2 to the fibrous corona, the most external subdomain of the kinetochore that expands in the absence of microtubule attachments to form crescent and ring structures ( Fig. 1 Biii; Kops and Gassmann, 2020 ). Checkpoint proteins, as well as the motors CENP-E and dynein, are known to localize to the fibrous corona.…”

Section: Viewpoint 3: Cyclin B1 Scaffolds Mad1 At the Kinetochore Cormentioning

confidence: 99%

Rashomon at the kinetochore: Function(s) of the Mad1–cyclin B1 complex

Houston

Lara-González

Desai

2020

Journal of Cell Biology

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In the film Rashomon, four witnesses describe seemingly contradictory views of one event. In a recent analogy, an interaction between the master mitotic regulator cyclin B1 and the spindle checkpoint component Mad1 was independently described by three groups who propose strikingly different functions for this interaction. Here, we summarize their findings and present a perspective on reconciling the different views.

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Crowning the Kinetochore: The Fibrous Corona in Chromosome Segregation

Cited by 58 publications

References 91 publications

Aurora B phosphorylates Bub1 to promote spindle assembly checkpoint signaling

Aurora B phosphorylates Bub1 to promote spindle assembly checkpoint signaling

SIK2 kinase synthetic lethality is driven by spindle assembly defects in FANCA‐deficient cells

Rashomon at the kinetochore: Function(s) of the Mad1–cyclin B1 complex

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