Too big not to fail: emerging evidence for size‐induced senescence

Manohar, Sandhya; Neurohr, Gabriel E.

doi:10.1111/febs.16983

Cited by 3 publications

(1 citation statement)

References 155 publications

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“…Based on the observation that having a nuclear compartment alters the cell cycle period, having very high or very low N/C ratios in cells could contribute to the deregulation of cell cycle progression, associated with altered cellular states involving aging and cancer (69). When cells increase their size, and the surface area-to-volume ratio decreases, their metabolic rate and regenerative capacity are reduced, triggering senescence (70)(71)(72)(73)(74). Opposite to senescence, in cancer, there is uncontrolled cell proliferation, and nuclear size has been a feature in the diagnosis and prognosis of different types of cancer (75)(76)(77)(78).…”

Section: Discussionmentioning

confidence: 99%

The nuclear-cytoplasmic ratio controls the cell cycle period in compartmentalized frog egg extract

Piñeros,

Frolov,

Ruiz-Reynés

et al. 2024

Preprint

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Each proliferating cell replicates its DNA and internal components before distributing this material evenly to its daughters. Although the regulation of cyclin-dependent kinases (Cdks) that dictate orderly cell cycle progression is well characterized, how the subcellular localization of the cell cycle machinery contributes to timing is not well understood. We investigated the influence of the nucleus by reconstituting cell cycle oscillations in droplets of frog egg extract in the absence or presence of a nuclear compartment and moni- toring dynamics by time-lapse microscopy. We found that the cell cycle time increased in the presence of nuclei, which grew larger with each cell cycle. The correlation between increasing nuclear volume and a longer cell cycle period was maintained across extracts and nuclei from various Xenopus species and persisted upon inhibition of DNA replication or transcription. However, inhibition of nuclear import or the kinase Wee1 impacted the relationship between the nuclear-cytoplasmic ratio and the cell cycle period. These experimental findings were reproduced in a computational model incorporating cell cycle oscillations, nuclear-cytoplasmic compart- mentalization, and periodic nuclear envelope breakdown and reformation. Altogether, our results support the major role of the nuclear compartment in setting the pace of the cell cycle and provide an explanation for the increase in cell cycle length observed at the midblastula transition when cells become smaller and the nuclear-cytoplasmic ratio increases.

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Section: Discussionmentioning

confidence: 99%

The nuclear-cytoplasmic ratio controls the cell cycle period in compartmentalized frog egg extract

Piñeros,

Frolov,

Ruiz-Reynés

et al. 2024

Preprint

View full text Add to dashboard Cite

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The search for CDK4/6 inhibitor biomarkers has been hampered by inappropriate proliferation assays

Foy,

Lew,

Saurin

2024

npj Breast Cancer

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CDK4/6 inhibitors are effective at treating advanced HR+ /HER2- breast cancer, however biomarkers that can predict response are urgently needed. We demonstrate here that previous large-scale screens designed to identify which tumour types or genotypes are most sensitive to CDK4/6 inhibitors have misrepresented the responsive cell lines because of a reliance on metabolic proliferation assays. CDK4/6-inhibited cells arrest in G1 but continue to grow in size, thereby producing more mitochondria. We show that this growth obscures the arrest using ATP-based proliferation assays but not if DNA-based assays are used instead. Furthermore, lymphoma lines, previously identified as the most sensitive, simply appear to respond the best using ATP-based assays because they fail to overgrow during the G1 arrest. Similarly, the CDK4/6 inhibitor abemaciclib appears to inhibit proliferation better than palbociclib because it also restricts cellular overgrowth through off-target effects. DepMap analysis of screening data using reliable assay types, demonstrates that palbociclib-sensitive cell types are also sensitive to Cyclin D1, CDK4 and CDK6 knockout/knockdown, whereas the palbociclib-resistant lines are sensitive to Cyclin E1, CDK2 and SKP2 knockout/knockdown. Potential biomarkers of palbociclib-sensitive cells are increased expression of CCND1 and RB1, and reduced expression of CCNE1 and CDKN2A. Probing DepMap with similar data from metabolic assays fails to reveal these associations. Together, this demonstrates why CDK4/6 inhibitors, and any other anti-cancer drugs that arrest the cell cycle but permit continued cell growth, must now be re-screened against a wide-range of cell types using an appropriate proliferation assay. This would help to better inform clinical trials and to identify much needed biomarkers of response.

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Single-cell imaging reveals a key role of Bck2 in budding yeast cell size adaptation to nutrient challenges

Chadha,

Kukhtevich,

Padovani

et al. 2024

Preprint

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Cell size is tightly controlled to optimize cell function and varies broadly depending on the organism, cell type, and environment. The budding yeast S. cerevisiae has been successfully used as a model to gain insights into eukaryotic cell size control. Multiple regulators of cell size in steady-state conditions have been identified, such as the G1/S transition activators Cln3 and Bck2 and the inhibitor Whi5. Individual deletions of these regulators result in populations with altered mean cell volumes. However, size homeostasis remains largely intact. Here, we show that although the roles of Bck2 and Cln3 for cell size regulation appear largely redundant in steady-state, a switch from fermentable to non-fermentable growth media reveals a unique role for Bck2 in cell size adaptation to changing nutrients. We use live-cell microscopy and machine learning-assisted image analysis to track single cells and their progeny through the nutrient switch. We find that after the switch, bck2del cells experience longer cell cycle arrests and more arrest associated enlargement than wild-type, whi5del or cln3del cells, indicating that Bck2 becomes the critical G1/S activator in changing nutrients. Our work demonstrates that studying size regulation during nutrient shifts to mimic the dynamic environments of free-growing microorganisms can resolve apparent redundancies observed in steady-state size regulation.

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Too big not to fail: emerging evidence for size‐induced senescence

Cited by 3 publications

References 155 publications

The nuclear-cytoplasmic ratio controls the cell cycle period in compartmentalized frog egg extract

The nuclear-cytoplasmic ratio controls the cell cycle period in compartmentalized frog egg extract

The search for CDK4/6 inhibitor biomarkers has been hampered by inappropriate proliferation assays

Single-cell imaging reveals a key role of Bck2 in budding yeast cell size adaptation to nutrient challenges

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