Control of cell proliferation by memories of mitosis

Meitinger, Franz; Davis, Robert L.; Martinez, Mallory B.; Shiau, Andrew K.; Oegema, Karen; Desai, Arshad

doi:10.1101/2022.11.14.515741

Cited by 5 publications

(9 citation statements)

References 54 publications

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“…One important conclusion of our study is that time measurement by the MSP does not directly involve the KT but it is a cytosolic process instead: an unknown mechanism favors the assembly of MSP protein complexes (53BP1 and p53 measured here by PLA, 53BP1:p53:USP28 measured by co‐immunoprecipitation in preprint: Meitinger et al , 2022). The physiological relevance of 53BP1 KT localization during normal mitosis instead remains to be established.…”

Section: Resultsmentioning

confidence: 78%

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PLK1 promotes the mitotic surveillance pathway by controlling cytosolic 53BP1 availability

Burigotto,

Vigorito,

Gliech

et al. 2023

EMBO Reports

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Abstract53BP1 acts at the crossroads between DNA repair and p53‐mediated stress response. With its interactors p53 and USP28, it is part of the mitotic surveillance (or mitotic stopwatch) pathway (MSP), a sensor that monitors the duration of cell division, promoting p53‐dependent cell cycle arrest when a critical time threshold is surpassed. Here, we show that Polo‐like kinase 1 (PLK1) activity is essential for the time‐dependent release of 53BP1 from kinetochores. PLK1 inhibition, which leads to 53BP1 persistence at kinetochores, prevents cytosolic 53BP1 association with p53 and results in a blunted MSP. Strikingly, the identification of CENP‐F as the kinetochore docking partner of 53BP1 enabled us to show that measurement of mitotic timing by the MSP does not take place at kinetochores, as perturbing CENP‐F‐53BP1 binding had no measurable impact on the MSP. Taken together, we propose that PLK1 supports the MSP by generating a cytosolic pool of 53BP1 and that an unknown cytosolic mechanism enables the measurement of mitotic duration.

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Section: Resultsmentioning

confidence: 78%

“…Ó 2023 The Authors EMBO reports 24: e57234 | 2023 Meitinger et al, 2022). The physiological relevance of 53BP1 KT localization during normal mitosis instead remains to be established.…”

Section: Interphase Mitosismentioning

confidence: 99%

PLK1 promotes the mitotic surveillance pathway by controlling cytosolic 53BP1 availability

Burigotto,

Vigorito,

Gliech

et al. 2023

EMBO Reports

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“…Work in the last 15 years have shown that cells not only possess a spindle checkpoint that monitors kinetochore-microtubule attachment in metaphase (for review see (51)), but also a mitotic duration surveillance mechanism, which induces a 53BP1/USP28-dependent activation of p53 to block the cell cycle when cells have spent more than 90 minutes in mitosis (26)(27)(28)(29)50). This ensures that cells that have encountered difficulties in satisfying the spindle assembly checkpoint are impaired in their proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…Instead, our in vitro and in vivo results indicate that a deregulation of microtubule minus-end dynamics, which leads to transient lagging chromosomes that elicit an Aurora-B dependent activation of 53PB1 and the p53- target p21, impairs cell cycle progression thus limiting the number of neuronal progenitor cells (see model Figure 5K). We postulate that this response is due to a surveillance mechanism that reacts to chromosomes that are not segregated in time with the rest of the chromosome mass in anaphase, complementing the mitotic surveillance mechanism that checks whether cells have remained for too long in mitosis ( 26–29 , 50 ). Given that loss of many cell division genes associated to primary microcephaly leads to transient lagging chromosomes, we speculate that this mechanism could be a frequent cause of this disease.…”

Section: Discussionmentioning

confidence: 99%

Transient lagging chromosomes cause primary microcephaly

Doria,

Ivanova,

Thomas

et al. 2024

Preprint

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Primary microcephaly is caused by the depletion of neuronal progenitor cells during brain development, resulting in reduced brain size and impaired cognitive abilities. It arises due to recessive loss-of-function mutations of cell division genes, that are thought to cause neuronal progenitor loss either because of aneuploidy-driven apoptosis, spindle orientation defects, or prolonged mitotic timing. Loss of the two most frequently impaired microcephaly genes, WDR62 and ASPM, elicits, however, none of these phenotypes in human cells. Instead, their loss slows down poleward microtubule flux and results in transient lagging chromosomes in anaphase. Whether these defects cause primary microcephaly is, however, unknown. Here we show that slower poleward microtubule flux rates lead to transient lagging anaphase chromosomes that elicit an Aurora-B dependent activation of 53BP1 and the p53-target p21, impairing cell proliferation. Co-depletion of CAMSAP1, an inhibitor of microtubule depolymerization at spindle poles, restores normal poleward flux rates, suppresses the lagging chromosomes, silences 53BP1 and p21 activation, and allows normal cell proliferation in WDR62-depleted cells. In Drosophila melanogaster larvae knock-down of the CAMSAP1 ortholog Patronin suppresses the small brain, the neuroblast depletion, and the impaired cognitive phenotype associated with WDR62 loss. We thus postulate that poleward microtubule flux defects in neuronal progenitor cells drive primary microcephaly due to the activation of 53BP1 and p21 in response to transient lagging chromosomes in anaphase. Since loss of most cell division genes associated with primary microcephaly can lead to such transient lagging chromosomes, we speculate that they might represent a common cause of this disease.

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“…Yet, Cyclin B1/Cdk1 is degraded and the SAC protein Mad2 is not localized to kinetochores in cells with a prolonged mitosis due to Cyclin A overexpression (den Elzen and Pines, 2001) suggesting a more complex scenario where Cyclin A/Cdk1 regulation of mitotic duration may be independent of active SAC signaling. In conclusion, to support timely mitotic progression and prevent genomic instability caused by a prolonged mitosis (Uetake and Sluder, 2010; Meitinger et al ., 2022) Cyclin A/Cdk1 activity is required in prometaphase, but its timely destruction is also required to prevent ongoing Cyclin A/Cdk1 function throughout prometaphase and potentially during later stages of mitosis.…”

Section: Discussionmentioning

confidence: 99%

Cyclin A/Cdk1 promotes chromosome alignment and timely mitotic progression

Valles,

Godek,

Compton

2023

Preprint

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To ensure genomic fidelity a series of spatially and temporally coordinated events are executed during prometaphase of mitosis, including bipolar spindle formation, chromosome attachment to spindle microtubules at kinetochores, the correction of erroneous kinetochore-microtubule (k-MT) attachments, and chromosome congression to the spindle equator. Cyclin A/Cdk1 kinase plays a key role in destabilizing k-MT attachments during prometaphase to promote correction of erroneous k-MT attachments. However, it is unknown if Cyclin A/Cdk1 kinase regulates other events during prometaphase. Here, we investigate additional roles of Cyclin A/Cdk1 in prometaphase by using an siRNA knockdown strategy to deplete endogenous Cyclin A from human cells. We find that depleting Cyclin A significantly extends mitotic duration, specifically prometaphase, because chromosome alignment is delayed. Unaligned chromosomes display erroneous monotelic, syntelic, or lateral k-MT attachments suggesting that bioriented k-MT attachment formation is delayed in the absence of Cyclin A. Mechanistically, chromosome alignment is likely impaired because the localization of the kinetochore proteins BUB1 kinase, KNL1, and MPS1 kinase are reduced in Cyclin A-depleted cells. Moreover, we find that Cyclin A promotes BUB1 kinetochore localization independently of its role in destabilizing k-MT attachments. Thus, Cyclin A/Cdk1 facilitates chromosome alignment during prometaphase to support timely mitotic progression.

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Control of cell proliferation by memories of mitosis

Cited by 5 publications

References 54 publications

PLK1 promotes the mitotic surveillance pathway by controlling cytosolic 53BP1 availability

PLK1 promotes the mitotic surveillance pathway by controlling cytosolic 53BP1 availability

Transient lagging chromosomes cause primary microcephaly

Cyclin A/Cdk1 promotes chromosome alignment and timely mitotic progression

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