Generation and Fates of Supernumerary Centrioles in Dividing Cells

Shin, Byungho; Kim, Myung Se; Lee, Yejoo; Jung, Gee In; Rhee, Kunsoo

doi:10.14348/molcells.2021.0220

Cited by 7 publications

(9 citation statements)

References 86 publications

(103 reference statements)

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“…Indeed, multipolar spindles were seen at exceedingly low frequencies in the setting of chronic KDM4A loss, likely due to the ability of surviving cells to cluster extra centrosomes at either pole during mitosis to compensate for the presence of supernumerary centrosomes. Multiple mechanisms exist for the generation of amplified centrosomes in cells ranging from overamplification, centrosome fragmentation, or failure to complete cytokinesis 14 . Although the supernumerary centrosomes observed in cells with a chronic loss of Kdm4a could arise via any of these approaches, our data with the KDM4A inhibitor, showing increased γ-tubulin puncta at the spindle within an hour of treatment with the inhibitor (JIB-04), is suggestive of a mechanism independent of aberrant S-phase centrosome replication.…”

Section: Discussionmentioning

confidence: 99%

Lysine Demethylase 4A is a Centrosome Associated Protein Required for Centrosome Integrity and Genomic Stability

Chowdhury,

Wang,

Love

et al. 2024

Preprint

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Centrosomes play a fundamental role in nucleating and organizing microtubules in the cell and are vital for faithful chromosome segregation and maintenance of genomic stability. Loss of structural or functional integrity of centrosomes causes genomic instability and is a driver of oncogenesis. The lysine demethylase 4A (KDM4A) is an epigenetic ‘eraser’ of chromatin methyl marks, which we show also localizes to the centrosome with single molecule resolution. We additionally discovered KDM4A demethylase enzymatic activity is required to maintain centrosome homeostasis, and is required for centrosome integrity, a new functionality unlinked to altered expression of genes regulating centrosome number. We find rather, that KDM4A interacts with both mother and daughter centriolar proteins to localize to the centrosome in all stages of mitosis. Loss ofKDM4Aresults in supernumerary centrosomes and accrual of chromosome segregation errors including chromatin bridges and micronuclei, markers of genomic instability. In summary, these data highlight a novel role for an epigenetic ‘eraser’ regulating centrosome integrity, mitotic fidelity, and genomic stability at the centrosome.

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Section: Discussionmentioning

confidence: 99%

Lysine Demethylase 4A is a Centrosome Associated Protein Required for Centrosome Integrity and Genomic Stability

Chowdhury,

Wang,

Love

et al. 2024

Preprint

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“…It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in The copyright holder for this this version posted September 30, 2022. ; https://doi.org/10.1101/2022.09.29.510042 doi: bioRxiv preprint providing a possible mechanistic explanation for their co-evolution in cancer cells. Multiple theories do exist pertaining to the origin centrosome cycle deregulation and appearance of supernumerary centrosomes in cancer cells, including cytokinesis failure, uncontrolled centriole duplication or elongation and PCM disintegration during mitosis 58,59 . Here, we speculate that a lack of synchrony between the centrosome and DNA cycle may also favour the appearance of abnormal centrosome number in cells experiencing persistent replication stress, as cells might accumulate dis-engaged centrioles that are prematurely licensed for centrosome duplication.…”

Section: Discussionmentioning

confidence: 99%

Mild replication stress causes premature centriole disengagement via a sub-critical Plk1 activity under the control of ATR-Chk1

Dwivedi

Harry

Meraldi

2022

Preprint

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A tight synchrony between the DNA and centrosome cycle is essential for genomic integrity. Centriole disengagement, which licenses centrosomes for duplication, occurs normally during mitotic exit. We recently demonstrated that mild DNA replication stress in untransformed human cells causes premature centriole disengagement at mitotic entry, leading to transient multipolar spindles that favour chromosome mis-segregation. How mild replication stress accelerate the centrosome cycle at the molecular level remained, however, unclear. Using expansion microscopy, we show that mild replication stress already induces premature centriole disengagement in G2 via the ATR-Chk1 axis of the DNA damage repair pathway. We demonstrate that this results in a subcritical Plk1 kinase activity that is insufficient for rapid mitotic entry. Nevertheless, it primes the pericentriolar matrix for Separase-dependent disassembly causing premature centriole disengagement in G2. We postulate that the differential requirement of Plk1 activity in the DNA and centrosome cycles explains how mild replication stress disrupts the synchrony between both processes and contributes to genomic instability.

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“…How do extra centrosomes arise in cancer? Several mechanisms can account for centrosome amplification, including dysregulated centrosome duplication, prolonged arrest in the G2 phase, cytokinesis failure, and increased centriole length (4,8,12,18). Dysregulation of the centrosome duplication cycle can lead to centriole overduplication, consequently generating supernumerary centrioles.…”

Section: The Origins Of Centrosome Amplificationmentioning

confidence: 99%

“…Defects in cell cycle progression, such as prolonged arrest in the G2 phase, induce centrosome reduplication (29,30); consistently, DNA damage can induce centrosome amplification by increasing the duration of the G2 phase (31,32). Centrosome amplification can arise from cytokinesis failure that generates tetraploid cells with twice the normal centrosome number and DNA content (4,8,12,18). Elongated centrioles can trigger centriole amplification (6), suggesting that structural centrosome defects can be linked to numerical defects, consistent with the observation that they often coexist in tumors (5,6).…”

Section: The Origins Of Centrosome Amplificationmentioning

confidence: 99%

“…How do cells tolerate the presence of extra centrosomes? Cells harboring extra centrosomes, if not organized, have the devastating potential of undergoing multipolar divisions that can produce inviable progenies due to gross chromosome missegregation (8,18,41). However, cells bearing supernumerary centrosomes escape this detrimental division and form pseudo-bipolar spindles by organizing extra centrosomes into two groups through the centrosome clustering process (Fig 1B) (23,(42)(43)(44).…”

Section: Tumorigenesismentioning

confidence: 99%

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Expanding roles of centrosome abnormalities in cancers

Song¹,

Jung²,

Kwon³

2023

BMB Rep

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Centrosome abnormalities are hallmarks of human cancers. Structural and numerical centrosome abnormalities correlate with tumor aggressiveness and poor prognosis, implicating that centrosome abnormalities could be a cause of tumorigenesis. Since Boveri made his pioneering recognition of the potential causal link between centrosome abnormalities and cancer more than a century ago, there has been significant progress in the field. Here, we review recent advances in the understanding of the causes and consequences of centrosome abnormalities and their connection to cancers. Centrosome abnormalities can drive the initiation and progression of cancers in multiple ways. For example, they can generate chromosome instability through abnormal mitosis, accelerating cancer genome evolution. Remarkably, it is becoming clear that the mechanisms by which centrosome abnormalities promote several steps of tumorigenesis are far beyond what Boveri had initially envisioned. We highlight various cancer-promoting mechanisms exerted by cells with centrosome abnormalities and how these cells possessing oncogenic potential can be monitored.

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Generation and Fates of Supernumerary Centrioles in Dividing Cells

Cited by 7 publications

References 86 publications

Lysine Demethylase 4A is a Centrosome Associated Protein Required for Centrosome Integrity and Genomic Stability

Lysine Demethylase 4A is a Centrosome Associated Protein Required for Centrosome Integrity and Genomic Stability

Mild replication stress causes premature centriole disengagement via a sub-critical Plk1 activity under the control of ATR-Chk1

Expanding roles of centrosome abnormalities in cancers

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