Cell size homeostasis is maintained by CDK4-dependent activation of p38 MAPK

Tan, Ceryl; Ginzberg, Miriam Bracha; Webster, Rachel L.; Iyengar, Seshu; Liu, Shixuan; Papadopoli, David; Concannon, John; Wang, Yuan; Auld, Douglas S.; Jenkins, Jeremy L.; Röst, Hannes L.; Topisirović, Ivan; Hilfinger, Andreas; Derry, W. Brent; Patel, Nish; Kafri, Ran

doi:10.1016/j.devcel.2021.04.030

Cited by 40 publications

(60 citation statements)

References 85 publications

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“…Time‐lapse imaging to quantify mitotic entries after drug addition showed that this proliferative arrest is associated with cell cycle delays that occurred prior to S‐phase because cells that had passed the restriction point entered mitosis at a normal rate for approximately the first 12 h of the movie (Fig 7A). Similar delays have recently been shown to occur in G1 upon partial CDK4/6 inhibition (Tan et al , 2021), an effect that we also see in RPE1‐FUCCI cells when the dose of palbociclib is decreased below 1 μM, allowing G1 to be extended for up to 3 days (Appendix Fig S6). We hypothesized that G1 delays could be problematic for cancer lines that are already subject to endogenous replication stress, therefore we quantified nuclear morphology and DNA damage in cells treated continuously with 1 µM palbociclib for up to 3 weeks.…”

Section: Resultssupporting

confidence: 86%

“…However, in addition to this, continual CDK4/6 inhibitor dosing could also induce genotoxic damage if this dose causes cell cycle delays instead of a complete G1 arrest, as we observed in a range of tumour types that cannot be fully arrested by palbociclib (Fig 7). We predict this damage is caused by extended G1 lengths that are induced by partial CDK4/6 inhibition (Tan et al , 2021) (Appendix Fig S6) and/or reductions in E2F targets that are required for S‐phase. Therefore, replication stress may be ongoing in patients during the periods of CDK4/6 inhibitor treatment, assuming that not all tumour cells will be held fully in G1 throughout this treatment period.…”

Section: Discussionmentioning

confidence: 95%

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CDK4/6 inhibitors induce replication stress to cause long‐term cell cycle withdrawal

et al. 2022

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CDK4/6 inhibitors arrest the cell cycle in G1‐phase. They are approved to treat breast cancer and are also undergoing clinical trials against a range of other tumour types. To facilitate these efforts, it is important to understand why a cytostatic arrest in G1 causes long‐lasting effects on tumour growth. Here, we demonstrate that a prolonged G1 arrest following CDK4/6 inhibition downregulates replisome components and impairs origin licencing. Upon release from that arrest, many cells fail to complete DNA replication and exit the cell cycle in a p53‐dependent manner. If cells fail to withdraw from the cell cycle following DNA replication problems, they enter mitosis and missegregate chromosomes causing excessive DNA damage, which further limits their proliferative potential. These effects are observed in a range of tumour types, including breast cancer, implying that genotoxic stress is a common outcome of CDK4/6 inhibition. This unanticipated ability of CDK4/6 inhibitors to induce DNA damage now provides a rationale to better predict responsive tumour types and effective combination therapies, as demonstrated by the fact that CDK4/6 inhibition induces sensitivity to chemotherapeutics that also cause replication stress.

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Section: Resultssupporting

confidence: 86%

Section: Discussionmentioning

confidence: 95%

CDK4/6 inhibitors induce replication stress to cause long‐term cell cycle withdrawal

et al. 2022

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“…2d, Supplementary Table 1). Importantly, we confirmed that large cells generated by long-term treatment with the CDK4/6 inhibitor Palbociclib, which arrests cells in G1 but does not inhibit cell growth 6,28 , recapitulated the proteome changes we observed in sizesorted G1 cells (Fig. 2e, Supplementary Table 2).…”

Section: Main Textsupporting

confidence: 79%

Increasing cell size remodels the proteome and promotes senescence

Lanz

Zatulovskiy

Swaffer

et al. 2021

Preprint

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Cell size is tightly controlled in healthy tissues, but it is poorly understood how cell size affects cell physiology. To address this, we measured how the proteome changes with cell size. Protein concentration changes are widespread, depend on the DNA-to-cell size ratio, and are predicted by subcellular localization, size-dependent mRNA concentrations, and protein turnover. As proliferating cells grow larger, concentration changes associated with cellular senescence are increasingly pronounced, suggesting that large size may be a cause rather than just a consequence of cell senescence. Consistent with this hypothesis, larger cells are prone to replicative-, DNA damage-, and CDK4/6i-induced senescence. More broadly, our findings show how cell size could impact many aspects of cell physiology through remodeling the proteome, thereby providing a rationale for cell size control to optimize cell function.

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“…The mechanisms driving such growth variations and their role in cell physiology remain mysterious. The molecular pathways underlying size homeostasis ( Tan et al, 2021 ; Liu et al, 2018 ; Zatulovskiy et al, 2020 ) may provide some explanations, but the identification and investigation of novel biosynthetic regulatory mechanisms may also be important. For example, the 15% increase in volume-specific growth rate in S-G2 may be the result of a similar increase in protein biosynthesis, but this would not meet the common expectations, given that both transcript levels ( Padovan-Merhar et al, 2015 ; Swaffer et al, 2021 ) and ribosome amounts ( Scott et al, 2010 ) scale linearly with cell volume – at least within the physiological range of cell volume ( Neurohr et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Volume growth in animal cells is cell cycle dependent and shows additive fluctuations

Cadart

Venkova

Piel

et al. 2022

eLife

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The way proliferating animal cells coordinate the growth of their mass, volume, and other relevant size parameters is a long-standing question in biology. Studies focusing on cell mass have identified patterns of mass growth as a function of time and cell cycle phase, but little is known about volume growth. To address this question, we improved our fluorescence exclusion method of volume measurement (FXm) and obtained 1700 single-cell volume growth trajectories of HeLa cells. We find that, during most of the cell cycle, volume growth is close to exponential and proceeds at a higher rate in S-G2 than in G1. Comparing the data with a mathematical model, we establish that the cell-to-cell variability in volume growth arises from constant-amplitude fluctuations in volume steps rather than fluctuations of the underlying specific growth rate. We hypothesize that such ‘additive noise’ could emerge from the processes that regulate volume adaptation to biophysical cues, such as tension or osmotic pressure.

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Cell size homeostasis is maintained by CDK4-dependent activation of p38 MAPK

Cited by 40 publications

References 85 publications

CDK4/6 inhibitors induce replication stress to cause long‐term cell cycle withdrawal

CDK4/6 inhibitors induce replication stress to cause long‐term cell cycle withdrawal

Increasing cell size remodels the proteome and promotes senescence

Volume growth in animal cells is cell cycle dependent and shows additive fluctuations

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