Mitotic Stress Is an Integral Part of the Oncogene-Induced Senescence Program that Promotes Multinucleation and Cell Cycle Arrest

Dikovskaya, Dina; Cole, John; Mason, Susan; Nixon, Colin; Karim, Saadia A.; McGarry, Lynn; Clark, William; Hewitt, Rachael N.; Sammons, Morgan A.; Zhu, Jiajun; Athineos, Dimitris; Leach, Joshua D.G.; Marchesi, Francesco; Tuyn, John van; Tait, Stephen W.G.; Brock, Claire; Morton, Jennifer P.; Wu, Hong Gyun; Berger, Shelley L.; Blyth, Karen; Adams, Peter D.

doi:10.1016/j.celrep.2015.07.055

Cited by 78 publications

(49 citation statements)

References 54 publications

(69 reference statements)

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“…Mcl‐1 has emerged as a major determinant of the cellular response to microtubule poisons that target mitotic cells (Harley et al , ; Shi et al , ; Wertz et al , ; Dikovskaya et al , ; Haschka et al , ; Topham et al , ; Sloss et al , ). Mcl‐1 is a member of the anti‐apoptotic Bcl‐2 family of proteins that suppress the activation of caspases, which are apoptotic proteases that bring about cellular destruction (Budihardjo et al , ).…”

Section: Introductionmentioning

confidence: 99%

Atypical APC/C‐dependent degradation of Mcl‐1 provides an apoptotic timer during mitotic arrest

et al. 2018

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The initiation of apoptosis in response to the disruption of mitosis provides surveillance against chromosome instability. Here, we show that proteolytic destruction of the key regulator Mcl‐1 during an extended mitosis requires the anaphase‐promoting complex or cyclosome (APC/C) and is independent of another ubiquitin E3 ligase, SCFFbw7. Using live‐cell imaging, we show that the loss of Mcl‐1 during mitosis is dependent on a D box motif found in other APC/C substrates, while an isoleucine‐arginine (IR) C‐terminal tail regulates the manner in which Mcl‐1 engages with the APC/C, converting Mcl‐1 from a Cdc20‐dependent and checkpoint‐controlled substrate to one that is degraded independently of checkpoint strength. This mechanism ensures a relatively slow but steady rate of Mcl‐1 degradation during mitosis and avoids its catastrophic destruction when the mitotic checkpoint is satisfied, providing an apoptotic timer that can distinguish a prolonged mitotic delay from normal mitosis. Importantly, we also show that inhibition of Cdc20 promotes mitotic cell death more effectively than loss of APC/C activity through differential effects on Mcl‐1 degradation, providing an improved strategy to kill cancer cells.

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Section: Introductionmentioning

confidence: 99%

Atypical APC/C‐dependent degradation of Mcl‐1 provides an apoptotic timer during mitotic arrest

et al. 2018

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“…1F and Supporting Fig. 1), which has been observed in senescent human melanocytes systems (28) and can result from aberrant mitotic progression in oncogene-induced senescence (29). Next, we tested for expression of the senescence markers p16 and p21.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of nucleotide synthesis promotes replicative senescence of human mammary epithelial cells

Delfarah

Parrish

et al. 2018

Preprint

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Cellular senescence is a mechanism by which cells permanently withdraw from the cell cycle in response to stresses including telomere shortening, DNA damage, or oncogenic signaling. Senescent cells contribute to both age-related degeneration and hyperplastic pathologies, including cancer. In culture, normal human epithelial cells enter senescence after a limited number of cell divisions, known as replicative senescence. Here, to investigate how metabolic pathways regulate replicative senescence, we used LC-MS-based metabolomics to analyze senescent primary human mammary epithelial cells (HMECs). We did not observe significant changes in glucose uptake or lactate secretion in senescent HMECs. However, analysis of intracellular metabolite pool sizes indicated that senescent cells exhibit depletion of metabolites from nucleotide synthesis pathways. Furthermore, stable isotope tracing with 13 C-labeled glucose or glutamine revealed a dramatic blockage of flux of these two metabolites into nucleotide synthesis pathways in senescent HMECs. To test whether cellular immortalization would reverse these observations, we expressed telomerase in HMECs. In addition to

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“…We demonstrate that in a natural aging cellular model, consisting of dermal fibroblasts retrieved from elderly donors and cultured under limited passage number to prevent replicative in vitro aging, senescent cells are mostly aneuploid as a result of defective chromosome mis-segregation. Nonetheless, as shown for oncogene-induced senescence and replicative senescence 52,53 , one round of cell division is likely required for a transition from ‘early’ to fully senescent state. Consistent with this idea of senescent state evolution, we found elderly mitotic cells to express SASP genes.…”

Section: Discussionmentioning

confidence: 99%

Molecular basis of mitotic decline during human aging

Macedo

Vaz

Bakker

et al. 2018

Preprint

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Aneuploidy, an abnormal chromosome number, has been linked to aging and age-20 associated diseases, but the underlying molecular mechanisms remain unknown. Supported by 21 direct live-cell imaging of young, middle-aged and old-aged primary human dermal fibroblasts, 22 we found that aneuploidy increases with aging due to general dysfunction of the mitotic Aging has been linked to an increase in aneuploidy for the past several decades 1 . This 34 association has been well documented for oocytes and is considered to be the main cause of 35 miscarriage and birth defects in humans 2 . However, aneuploidy can also arise in somatic cells, 36 and a number of studies have reported age-dependent increases in aneuploidy [3][4][5][6][7] . These studies 37 have shown that aging is positively correlated with the incidence of chromosome mis- The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/261008 doi: bioRxiv preprint first posted online Feb. 6, 2018; and the lower mitotic indexes of elderly cell cultures has limited these studies from clearly 43 demonstrating whether mitotic genes are repressed intrinsically in old dividing cells. Moreover, 44 analysis of the mitotic process in aging models and diseases has been scarce and a 45 comprehensive analysis of cell division efficiency in naturally aged cells is largely missing. 46More recently, aneuploidy has been also linked to aging. Studies of aneuploidy-prone mouse 47 models exhibiting increased rates of chromosome mis-segregation uncovered a unanticipated 48 nexus with the rate of aging and the development of age-related pathologies [11][12][13][14] Results 72Aneuploidy increases during natural aging 73In our study we used human dermal fibroblasts (HDFs) collected from healthy Caucasian males 74 with ages ranging from neonatal to octogenarian ( Supplementary Fig.1a), to test whether The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/261008 doi: bioRxiv preprint first posted online Feb. 6, 2018; strict quantitative parameters by microscopy analysis, in the proliferating fibroblast cultures from 89 older individuals and the HGPS patient ( Supplementary Fig.1b-g), thus validating their 90 suitability as models of advanced and premature aging, respectively. 91To determine if aneuploidy increases with aging, we performed fluorescence in situ 92 hybridization (FISH) analysis for three chromosome pairs. We found significantly higher 93 aneusomy indexes in asynchronous cell populations of middle-aged, old-aged and progeria 94 samples (Fig. 1a,b). However, because aneuploid cells are most likely outcompeted in culture by 95 diploid cells 17 , thereby diluting the aneuploidy index, we additionally measured aneuploidy in a 96 post-mitotic cell subpopulation generated during a 24h treatment with the cytokinesis inhibitor 97 cytochalasin D (Fig. 1a,c). Using this approach, we observed even higher aneuploidy in the 98 middle-aged, old-aged and progeria cultures. Thus, the mild aneuploidy levels found ...

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Mitotic Stress Is an Integral Part of the Oncogene-Induced Senescence Program that Promotes Multinucleation and Cell Cycle Arrest

Cited by 78 publications

References 54 publications

Atypical APC/C‐dependent degradation of Mcl‐1 provides an apoptotic timer during mitotic arrest

Atypical APC/C‐dependent degradation of Mcl‐1 provides an apoptotic timer during mitotic arrest

Inhibition of nucleotide synthesis promotes replicative senescence of human mammary epithelial cells

Molecular basis of mitotic decline during human aging

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