Chromosome mis-segregation and cytokinesis failure in trisomic human cells

The Poly(A) Tail Length (PATL) of mRNAs of certain cell-cycle regulatory genes undergo significant trimming during M-phase, however the functional importance is unknown. The Ccr4-Not and PAN complexes account for the majority of cytoplasmic poly(A) deadenylation, but their potential roles in regulation of cell-cycle mRNA PATLs has not been investigated. We find that under conditions of microtubule stress in yeast, loss of PAN deadenylase activity leads to arrest in M phase, defective spindles, and increased cell death. PAN consists of the catalytic subunit Pan2 and the RNA binding subunit Pan3. Consistent with a role in mitosis, PAN2 interacts genetically with tubulin genes, prefoldin complex genes and the cyclins CLB1 and CLN3. PAN2 knockdown in human cultured cells disrupts mitosis and results in spindle fragmentation leading to abnormal cell division, while expression of human PAN2 in yeast rescues pan2Δ cell-cycle phenotypes. Hence, we reveal an important highly conserved role for PAN in ensuring proper mitosis when cells are under microtubule stress. We propose PAN regulates PATLs of mRNAs of key cell-cycle/mitotic proteins in response to defective spindles.

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Compromised Mitotic Fidelity in Human Pluripotent Stem Cells

Milagre¹,

Pereira²,

Oliveira³

2023

Preprint

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Human pluripotent stem cells (PSCs), which include both embryonic and induced pluripotent stem cells, are widely used in fundamental and applied biomedical research. They have been instrumental for better understanding development and cell differentiation processes, disease origin and progression, and can aid in the discovery of new drugs. PSCs also hold great potential in regenerative medicine to treat or diminish the effects of certain debilitating diseases, such as degenerative disorders. However, some concerns have recently been raised over their safety for the use in regenerative medicine. One of the major concerns is the fact that PSCs are prone to errors in passing the correct number of chromosomes to daughter cells, resulting in aneuploid cells. Aneuploidy, characterised by an imbalance in chromosome number, elicits the upregulation of different stress pathways that are deleterious to cell homeostasis, impair proper embryo development and can potentiate cancer development. In this review we will summarise known molecular mechanisms recently revealed to impair mitotic fidelity in human PSCs and the consequences of the decreased mitotic fidelity of these cells. We will finish with speculative views on how the physiological characteristics of PSCs can affect the mitotic machinery and how their suboptimal mitotic fidelity may be circumvented.

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Spatial Variation of Microtubule Depolymerization in Large Asters Suggests Regulation by MAP Depletion

Ishihara

Decker

Caldas

et al. 2020

Preprint

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AbstractMicrotubule plus end depolymerization rate is a potentially important target of physiological regulation, but it has been challenging to measure, so its role in spatial organization is poorly understood. Here we apply a method for tracking plus ends based on time difference imaging to measure depolymerization rates in large interphase asters growing in Xenopus egg extract. We observed strong spatial regulation of depolymerization rates, which were almost two-fold higher in the aster interior compared to the periphery, and much less regulation of polymerization or catastrophe rates. We interpret these data in terms of a limiting component model, where aster growth results in lower levels of soluble tubulin and MAPs in the interior cytosol compared to that at the periphery. The steady-state polymer fraction of tubulin was ∼30%, so tubulin is not strongly depleted in the aster interior. We propose that the limiting component for microtubule assembly is a MAP that inhibits depolymerization, and that egg asters are tuned to low microtubule density.

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Recent insights into the causes and consequences of chromosome mis-segregation

Devillers,

dos Santos,

Destombes

et al. 2024

Oncogene

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Reduction of chromosomal instability and inflammation is a common aspect of adaptation to aneuploidy

Hintzen,

Schubert,

Soto

et al. 2024

EMBO Rep

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Aneuploidy, while detrimental to untransformed cells, is notably prevalent in cancer. Aneuploidy is found as an early event during tumorigenesis which indicates that cancer cells have the ability to surmount the initial stress responses associated with aneuploidy, enabling rapid proliferation despite aberrant karyotypes. To generate more insight into key cellular processes and requirements underlying adaptation to aneuploidy, we generated a panel of aneuploid clones in p53-deficient RPE-1 cells and studied their behavior over time. As expected, de novo-generated aneuploid clones initially display reduced fitness, enhanced levels of chromosomal instability (CIN), and an upregulated inflammatory response. Intriguingly, after prolonged culturing, aneuploid clones exhibit increased proliferation rates while maintaining aberrant karyotypes, indicative of an adaptive response to the aneuploid state. Interestingly, all adapted clones display reduced CIN and reduced inflammatory signaling, suggesting that these are common aspects of adaptation to aneuploidy. Collectively, our data suggests that CIN and concomitant inflammation are key processes that require correction to allow for fast proliferation in vitro. Finally, we provide evidence that amplification of oncogenic KRAS can promote adaptation.

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Chromosome mis-segregation and cytokinesis failure in trisomic human cells

Cited by 97 publications

References 74 publications

Jumping translocation involving chromosome 13q in a patient with Crohn's Disease and inv(16)(p13.1q22)/CBFB-MYH11 acute myeloid leukemia

Chromosome instability and aneuploidy in the mammalian brain

PAN deadenylase ensures proper mitosis under conditions of microtubule stress by regulating spindle integrity and promoting cell survival

Compromised Mitotic Fidelity in Human Pluripotent Stem Cells

Spatial Variation of Microtubule Depolymerization in Large Asters Suggests Regulation by MAP Depletion

Recent insights into the causes and consequences of chromosome mis-segregation

Reduction of chromosomal instability and inflammation is a common aspect of adaptation to aneuploidy

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