Autophagy Plays a Critical Role in the Degradation of Active RHOA, the Control of Cell Cytokinesis, and Genomic Stability

Belaïd, Amine; Cerezo, Michaël; Chargui, Abderrahman; Corcelle-Termeau, Elisabeth; Pédeutour, Florence; Giuliano, Sandy; Ilié, Marius; Rubera, Isabelle; Tauc, Michel; Barale, Sophie; Bertolotto, Corine; Brest, Patrick; Vouret‐Craviari, Valérie; Klionsky, Daniel J.; Carle, Georges F.; Hofman, Paul; Mograbi, Baharia

doi:10.1158/0008-5472.can-12-4142

Cited by 94 publications

(113 citation statements)

References 51 publications

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“…When autophagy is disrupted, active RHOA accumulates in areas surrounding the midbody and causes cytokinesis failure, multinucleation, and aneuploidy. 31 While changes in DNA repair mechanisms and cell cycle progression could potentially influence the extent and pattern of telomere fusions, we find no change in these readouts despite the complete loss of autophagic activity in immortalized atg5 or atg7 knockout MEFs. Thus, autophagy does not influence telomere dysfunction-induced genome instability in this cellular context.…”

Section: Discussioncontrasting

confidence: 52%

“…28,29 Moreover, autophagy guards against aneuploidy by regulating cell cycle progression and cytokinesis. 30,31 In light of these emerging roles for autophagy in senescence and genome instability, 2 critical sequelae of telomere dysfunction, we sought to delineate the potential functions of autophagy in the cellular response to acute telomere dysfunction. Our results reveal the autophagy-independent nature of senescence and genome instability driven by targeted telomere dysfunction.…”

Section: Introductionmentioning

confidence: 99%

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Autophagy-independent senescence and genome instability driven by targeted telomere dysfunction

Mar¹,

Debnath²,

Stohr³

2015

Autophagy

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Abbreviations: ACD/Tpp1, adrenocortical dysplasia homolog (mouse); ATG5, autophagy-related 5, ATG7, autophagy-related 7; B2M, b-2-microglobulin; HBSS, Hank's buffered salt solution; HMECs, human mammary epithelial cells; MEFs, mouse embryonic fibroblasts; MT-HsTER, mutant template-Homo sapiens template-containing RNA; MT-MmTER, mutant template-Mus musculus template-containing RNA; OIS, oncogene-induced senescence; RBBP8/CtIP, retinoblastoma binding protein 8; SA-b-Gal, senescence-associated b-galactosidase; SASP, senescence associated secretory phenotype; TDIS, telomere dysfunction-induced senescence; TERT, telomerase reverse transcriptase; TIFs, telomere dysfunction-induced foci.Telomere dysfunction plays a complex role in tumorigenesis. While dysfunctional telomeres can block the proliferation of incipient cancer clones by inducing replicative senescence, fusion of dysfunctional telomeres can drive genome instability and oncogenic genomic rearrangements. Therefore, it is important to define the regulatory pathways that guide these opposing effects. Recent work has shown that the autophagy pathway regulates both senescence and genome instability in various contexts. Here, we apply models of acute telomere dysfunction to determine whether autophagy modulates the resulting genome instability and senescence responses. While telomere dysfunction rapidly induces autophagic flux in human fibroblast cell lines, inhibition of the autophagy pathway does not have a significant impact upon the transition to senescence, in contrast to what has previously been reported for oncogene-induced senescence. Our results suggest that this difference may be explained by disparities in the development of the senescence-associated secretory phenotype. We also show that chromosome fusions induced by telomere dysfunction are comparable in autophagy-proficient and autophagy-deficient cells. Altogether, our results highlight the complexity of the senescence-autophagy interface and indicate that autophagy induction is unlikely to play a significant role in telomere dysfunction-driven senescence and chromosome fusions.

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Section: Discussioncontrasting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Autophagy-independent senescence and genome instability driven by targeted telomere dysfunction

Mar¹,

Debnath²,

Stohr³

2015

Autophagy

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“…22 Autophagy was also recently shown to play a critical role in the degradation of active RhoA, with implications for cytokinesis control and genomic stability. 52 Defects in autophagy specifically drove cytokinesis failure, multinucleation and aneuploidy in correlation with the failure of RhoA to localize at the midbody, accumulating in autolysosomes instead. 52 Furthermore, constitutively active RhoA was found to inhibit proliferation by retarding cell cycle progression and impairing cytokinesis.…”

Section: Discussionmentioning

confidence: 99%

“…52 Defects in autophagy specifically drove cytokinesis failure, multinucleation and aneuploidy in correlation with the failure of RhoA to localize at the midbody, accumulating in autolysosomes instead. 52 Furthermore, constitutively active RhoA was found to inhibit proliferation by retarding cell cycle progression and impairing cytokinesis. 48 Thus, it is possible that TPC1 contributes to cytokinesis control by regulating RhoA recycling via lysosomal autophagy.…”

Section: Discussionmentioning

confidence: 99%

Two-pore channel 1 interacts with citron kinase, regulating completion of cytokinesis

et al. 2015

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Two-pore channels (TPC1, 2, and 3) are recently identified endolysosmal ion channels, but remain poorly characterized. In this study, we show for the first time a role for TPC1 in cytokinesis, the final step in cell division. HEK 293 T-REx cells inducibly overexpressing TPC1 demonstrated a lack of proliferation accompanied by multinucleation and an increase in G2/M cycling cells. Increased TPC1 was associated with a concomitant accumulation of active RhoGTP and a decrease in phosphorylated myosin light chain (MLC). Finally, we demonstrated a novel interaction between TPC1 and citron kinase (CIT). These results identify TPC1 as a central component of cytokinetic control, specifically during abscission, and introduce a means by which the endolysosomal system may play an active role in this process.

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“…Autophagy has been proposed to maintain genomic stability through the degradation of the GTPase RhoA. The elevated expression of RhoA was positively correlated with autophagic dysfunction in human lung carcinoma (10). Induction of autophagy through mTOR inhibitors has been associated with radiosensitization in NSCLC cells (75).…”

Section: Autophagy and Lung Cancermentioning

confidence: 99%

Autophagy: A Crucial Moderator of Redox Balance, Inflammation, and Apoptosis in Lung Disease

Nakahira

Cloonan

Mizumura

et al. 2014

Antioxidants & Redox Signaling

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Significance: Autophagy is a fundamental cellular process that functions in the turnover of subcellular organelles and protein. Activation of autophagy may represent a cellular defense against oxidative stress, or related conditions that cause accumulation of damaged proteins or organelles. Selective forms of autophagy can maintain organelle populations or remove aggregated proteins. Autophagy can increase survival during nutrient deficiency and play a multifunctional role in host defense, by promoting pathogen clearance and modulating innate and adaptive immune responses. Recent Advances: Autophagy has been described as an inducible response to oxidative stress. Once believed to represent a random process, recent studies have defined selective mechanisms for cargo assimilation into autophagosomes. Such mechanisms may provide for protein aggregate detoxification and mitochondrial homeostasis during oxidative stress. Although long studied as a cellular phenomenon, recent advances implicate autophagy as a component of human diseases. Altered autophagy phenotypes have been observed in various human diseases, including lung diseases such as chronic obstructive lung disease, cystic fibrosis, pulmonary hypertension, and idiopathic pulmonary fibrosis. Critical Issues: Although autophagy can represent a pro-survival process, in particular, during nutrient starvation, its role in disease pathogenesis may be multifunctional and complex. The relationship of autophagy to programmed cell death pathways is incompletely defined and varies with model system. Future Directions: Activation or inhibition of autophagy may be used to alter the progression of human diseases. Further resolution of the mechanisms by which autophagy impacts the initiation and progression of diseases may lead to the development of therapeutics specifically targeting this pathway. Antioxid. Redox Signal. 20,

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Autophagy Plays a Critical Role in the Degradation of Active RHOA, the Control of Cell Cytokinesis, and Genomic Stability

Cited by 94 publications

References 51 publications

Autophagy-independent senescence and genome instability driven by targeted telomere dysfunction

Autophagy-independent senescence and genome instability driven by targeted telomere dysfunction

Two-pore channel 1 interacts with citron kinase, regulating completion of cytokinesis

Autophagy: A Crucial Moderator of Redox Balance, Inflammation, and Apoptosis in Lung Disease

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