Consequences of mitotic failure – The penalties and the rewards

Storchová, Zuzana

doi:10.1016/j.semcdb.2021.03.007

Cited by 8 publications

(5 citation statements)

References 141 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Topology 102 or the assembly mechanism 101 are factors for dosage-sensitivity. Aneuploidy has been associated to cellular stress, altered proteostasis, and both sensitivity and resistance to therapy 73,[103][104][105] . While aneuploidy is a common feature of ATCs 73 , we did not observe a direct link between aneuploidy and PIAS2b-dsRNAi response.…”

Section: Discussionmentioning

confidence: 99%

dsRNAi-mediated silencing of PIAS2beta specifically kills anaplastic carcinomas by mitotic catastrophe

Rodrigues,

Chenlo,

Bravo

et al. 2024

Nat Commun

View full text Add to dashboard Cite

The E3 SUMO ligase PIAS2 is expressed at high levels in differentiated papillary thyroid carcinomas but at low levels in anaplastic thyroid carcinomas (ATC), an undifferentiated cancer with high mortality. We show here that depletion of the PIAS2 beta isoform with a transcribed double-stranded RNA–directed RNA interference (PIAS2b-dsRNAi) specifically inhibits growth of ATC cell lines and patient primary cultures in vitro and of orthotopic patient-derived xenografts (oPDX) in vivo. Critically, PIAS2b-dsRNAi does not affect growth of normal or non-anaplastic thyroid tumor cultures (differentiated carcinoma, benign lesions) or cell lines. PIAS2b-dsRNAi also has an anti-cancer effect on other anaplastic human cancers (pancreas, lung, and gastric). Mechanistically, PIAS2b is required for proper mitotic spindle and centrosome assembly, and it is a dosage-sensitive protein in ATC. PIAS2b depletion promotes mitotic catastrophe at prophase. High-throughput proteomics reveals the proteasome (PSMC5) and spindle cytoskeleton (TUBB3) to be direct targets of PIAS2b SUMOylation at mitotic initiation. These results identify PIAS2b-dsRNAi as a promising therapy for ATC and other aggressive anaplastic carcinomas.

show abstract

Section: Discussionmentioning

confidence: 99%

dsRNAi-mediated silencing of PIAS2beta specifically kills anaplastic carcinomas by mitotic catastrophe

Rodrigues,

Chenlo,

Bravo

et al. 2024

Nat Commun

View full text Add to dashboard Cite

show abstract

“…Mitosis is a highly coordinated process to assure the fidelity of chromosome segregation, which is crucial for genome stability and cellular fitness ( Pavin and Tolić, 2016 ; Nam et al, 2015 ). Conversely, chromosome missegregation induces aneuploidy, lethality, or malignant transformation ( Ben-David and Amon, 2020 ; Storchova, 2021 ). The fidelity of chromosome segregation involves interdependent processes at the kinetochore–microtubule interface and the spindle assembly checkpoint ( Navarro and Cheeseman, 2021 ; Jia et al, 2013 ; Mansfeld et al, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

UHRF1 promotes spindle assembly and chromosome congression by catalyzing EG5 polyubiquitination

Qi,

Liu,

Peng

et al. 2023

Journal of Cell Biology

View full text Add to dashboard Cite

UHRF1 is an epigenetic coordinator bridging DNA methylation and histone modifications. Additionally, UHRF1 regulates DNA replication and cell cycle, and its deletion induces G1/S or G2/M cell cycle arrest. The roles of UHRF1 in the regulation of G2/M transition remain poorly understood. UHRF1 depletion caused chromosome misalignment, thereby inducing cell cycle arrest at mitotic metaphase, and these cells exhibited the defects of spindle geometry, prominently manifested as shorter spindles. Mechanistically, UHRF1 protein directly interacts with EG5, a kinesin motor protein, during mitosis. Furthermore, UHRF1 induced EG5 polyubiquitination at the site of K1034 and further promoted the interaction of EG5 with spindle assembly factor TPX2, thereby ensuring accurate EG5 distribution to the spindles during metaphase. Our study clarifies a novel UHRF1 function as a nuclear protein catalyzing EG5 polyubiquitination for proper spindle architecture and faithful genomic transmission, which is independent of its roles in epigenetic regulation and DNA damage repair inside the nucleus. These findings revealed a previously unknown mechanism of UHRF1 in controlling mitotic spindle architecture and chromosome behavior and provided mechanistic evidence for UHRF1 deletion-mediated G2/M arrest.

show abstract

“…Mitotic errors can result in altered chromosome numbers, either by missegregating one or a few chromosomes leading to aneuploidy, or by mitotic slippage, exit from mitosis without executing anaphase or completing cytokinesis, leading to tetraploidization. Both types of errors present further challenges, including genomic instability and cellular stress (Chunduri & Storchová, 2019 ; Storchova, 2021 ). Aneuploidy has profound effects on cellular physiology, and in most contexts, it is detrimental (Gordon et al , 2012 ; Santaguida et al , 2017 ).…”

Section: Introductionmentioning

confidence: 99%

The GCN2/eIF2αK stress kinase regulates PP1 to ensure mitotic fidelity

Stonyte,

Mastrangelopoulou,

Timmer

et al. 2023

EMBO Reports

View full text Add to dashboard Cite

GCN2/eIF2αK4 is exclusively seen as an eIF2α kinase, which regulates reprogramming of protein translation in response to stress. Here, we show that GCN2 has an unexpected role in unstressed cells as a regulator of mitosis. This function is not through its canonical role in translation reprogramming, but through the regulation of two previously unidentified substrates, PP1α and γ. In the absence of GCN2 function, timing and levels of phosphorylation of key mitotic players are altered, leading to aberrant chromosome alignment, missegregating chromosomes, elevated number of tripolar spindles, and a delay in progression through mitosis. Pharmacological inhibition of GCN2 results in similar effects and is synergistic with Aurora A inhibition in causing more severe mitotic errors and cell death. We suggest that GCN2‐dependent phosphorylation of PP1α and γ restrains their activity and this is important to ensure the timely regulation of phosphorylation of several PP1 substrates during early mitosis. These findings highlight a druggable PP1 inhibitor and open new avenues of research on the therapeutic potential of GCN2 inhibitors.

show abstract

Consequences of mitotic failure – The penalties and the rewards

Cited by 8 publications

References 141 publications

dsRNAi-mediated silencing of PIAS2beta specifically kills anaplastic carcinomas by mitotic catastrophe

dsRNAi-mediated silencing of PIAS2beta specifically kills anaplastic carcinomas by mitotic catastrophe

UHRF1 promotes spindle assembly and chromosome congression by catalyzing EG5 polyubiquitination

The GCN2/eIF2αK stress kinase regulates PP1 to ensure mitotic fidelity

Contact Info

Product

Resources

About