Increasing cell size remodels the proteome and promotes senescence

Lanz, Michael; Zatulovskiy, Evgeny; Swaffer, Matthew P.; Zhang, Lichao; Zhang, Shuyuan; You, Dong Shin; Marinov, Georgi K.; McAlpine, Patrick L.; Elias, Joshua E.; Skotheim, Jan M.

doi:10.1101/2021.07.29.454227

Cited by 38 publications

(103 citation statements)

References 59 publications

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“…This is in line with recent work in yeast, which shows that an increase in cell volume beyond a particular point causes ‘cytoplasmic dilution’ and permanent cell-cycle exit (Neurohr et al ., 2019). More recent work in mammalian cells also indicates that increasing cell size itself results in proteomic changes that gradually approach those found in senescent cells, supporting our hypothesis that cellular growth signalling that drives an increase in cell size per se promotes senescence (Lanz et al ., 2021). Interestingly, this study shows that an increase in cell size promotes senescence in cells where the cell cycle is arrested via the CDK4/6 inhibitor palbociclib.…”

Section: Discussionsupporting

confidence: 86%

Active growth signalling promotes cancer cell sensitivity to the CDK7 inhibitor ICEC0942

Wilson

Sava

Vuina

et al. 2021

Preprint

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CDK7 has a central role in promoting cellular proliferation, through the activation of the mi-totic CDKs, and by driving global gene expres-sion, through targeting RNA polymerase II. Several recently developed CDK7 inhibitors (CDK7i) have been shown to be non-toxic and to limit tumour growth for a number of cancer cell types and are now in Phase I/II clinical tri-als. However, the mechanisms underlying the sensitivity of particular cancer cells to CDK7 inhibition remain largely unknown. To improve the outcome of individual patients and increase the chances of successful CDK7i approval, we assessed which fundamental cellu-lar processes determine sensitivity to CDK7 in-hibition, using the highly specific CDK7 inhibi-tor ICEC0942. Our data shows that selective CDK7 inhibition acutely arrests cells in the G1 phase of the cell cycle, which over time leads to senescence. Through a genome-wide CRISPR knock-out chemogenetic screen we identified active mTOR (mammalian target of rapamycin) signalling, as an important determinant of ICEC0942-induced senescence and show that a cancer-associated mutation that promotes cell growth can increase sensitivity to ICEC0942. Our work indicates that cellular growth is an important predictive marker for sensitivity to CDK7i.

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Section: Discussionsupporting

confidence: 86%

Active growth signalling promotes cancer cell sensitivity to the CDK7 inhibitor ICEC0942

Wilson

Sava

Vuina

et al. 2021

Preprint

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“…Nearly all proteins (3132/3171, 99%) displayed a relative change between -1 and 1, indicating that concentrations maximally halve or double when cells double in size as within a normal cell cycle. This scaling analysis confirmed the previously observed dilution of the retinoblastoma protein RB1 (3) as well as histones (16). Unexpectedly, these proteins were neither unique nor the most diluted ones.…”

Section: Introductionsupporting

confidence: 89%

“…Consistent with the proteomics data, we observed dilution of RB1, MCM2 as well as RPL9 as a representative of the ribosomal subunits within the ~2-fold average volume differences between the smallest and largest subpopulations. It has been reported that RB1 and histone concentrations are transcriptionally regulated (3,16), but whether the overall proteome scaling is transcriptionally regulated is not known. To test this, we analysed scaling using NCI60 RNAseq data (15) and compared this to the proteome scaling.…”

Section: Introductionmentioning

confidence: 99%

Size-scaling promotes senescence-like changes in proteome and organelle content

Cheng

Chen

Kong

et al. 2021

Preprint

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Senescent cells typically have an enlarged cell size but the reason for this has not been fully elucidated. As abnormal cell size may alter protein concentrations and cellular functionality, we used proteomic data from 59 unperturbed human cell lines to systematically characterize cell-size dependent changes in intracellular protein concentrations and organelle content. Increase in cell size leads to ubiquitous transcriptionally and post-transcriptionally regulated reorganization and dilution of the proteome. Many known senescence proteins display disproportionate size-scaling consistent with their altered expression in senescent cells, while lysosomes and the endoplasmic reticulum expand in larger cells contributing to the senescence phenotype. Analysis of organelle proteome expression identifies p53 and retinoblastoma pathways as mediators of size-scaling, consistent with their role in senescence. Taken together, cell size can alter cellular fitness and function through cumulative reorganization of the proteome and organelle content. An extreme consequence of this pervasive size-scaling appears to be senescence.

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“…In line with accelerated cell aging, HF-MSS showed a downregulation of histone proteins, a well-recognized sign of senescence [28]. Importantly, one of the key features of senescent cells is their increased size [29]. These results, and the fact that the HF-MSS proliferation rate was reduced, suggest that these cells achieve a sort of senescent state in order to survive.…”

Section: Discussionmentioning

confidence: 80%

Proteomic Analysis of Marinesco–Sjogren Syndrome Fibroblasts Indicates Pro-Survival Metabolic Adaptation to SIL1 Loss

Potenza

Cufaro

Biase

et al. 2021

IJMS

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Marinesco–Sjogren syndrome (MSS) is a rare multisystem pediatric disorder, caused by loss-of-function mutations in the gene encoding the endoplasmic reticulum cochaperone SIL1. SIL1 acts as a nucleotide exchange factor for BiP, which plays a central role in secretory protein folding. SIL1 mutant cells have reduced BiP-assisted protein folding, cannot fulfil their protein needs, and experience chronic activation of the unfolded protein response (UPR). Maladaptive UPR may explain the cerebellar and skeletal muscle degeneration responsible for the ataxia and muscle weakness typical of MSS. However, the cause of other more variable, clinical manifestations, such as mild to severe mental retardation, hypogonadism, short stature, and skeletal deformities, is less clear. To gain insights into the pathogenic mechanisms and/or adaptive responses to SIL1 loss, we carried out cell biological and proteomic investigations in skin fibroblasts derived from a young patient carrying the SIL1 R111X mutation. Despite fibroblasts not being overtly affected in MSS, we found morphological and biochemical changes indicative of UPR activation and altered cell metabolism. All the cell machineries involved in RNA splicing and translation were strongly downregulated, while protein degradation via lysosome-based structures was boosted, consistent with an attempt of the cell to reduce the workload of the endoplasmic reticulum and dispose of misfolded proteins. Cell metabolism was extensively affected as we observed a reduction in lipid synthesis, an increase in beta oxidation, and an enhancement of the tricarboxylic acid cycle, with upregulation of eight of its enzymes. Finally, the catabolic pathways of various amino acids, including valine, leucine, isoleucine, tryptophan, lysine, aspartate, and phenylalanine, were enhanced, while the biosynthetic pathways of arginine, serine, glycine, and cysteine were reduced. These results indicate that, in addition to UPR activation and increased protein degradation, MSS fibroblasts have profound metabolic alterations, which may help them cope with the absence of SIL1.

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Increasing cell size remodels the proteome and promotes senescence

Cited by 38 publications

References 59 publications

Active growth signalling promotes cancer cell sensitivity to the CDK7 inhibitor ICEC0942

Active growth signalling promotes cancer cell sensitivity to the CDK7 inhibitor ICEC0942

Size-scaling promotes senescence-like changes in proteome and organelle content

Proteomic Analysis of Marinesco–Sjogren Syndrome Fibroblasts Indicates Pro-Survival Metabolic Adaptation to SIL1 Loss

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