Kinetic Analysis of Protein Stability Reveals Age-Dependent Degradation

McShane, Erik; Sin, Celine; Zauber, Henrick; Wells, Justin; Donnelly, Neysan; Wang, Xi; Hou, Jingyi; Chen, Wei; Storchová, Zuzana; Marsh, Joseph A.; Valleriani, Angelo; Selbach, Matthias

doi:10.1016/j.cell.2016.09.015

Cited by 290 publications

(352 citation statements)

References 70 publications

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“…Aneuploid chromosomes are transcribed and translated proportional to their copy number (Dephoure et al, 2014; Stingele et al, 2012; Torres et al, 2007, 2010), which can lead to stoichiometric imbalances in endogenous proteins and protein complexes (Oromendia et al, 2012; Sheltzer and Amon, 2011). To compensate, cells rely on a set of protein quality control mechanisms, including the HSF1/HSP90 folding pathway (Donnelly et al, 2014; Oromendia et al, 2012), autophagy, and proteasomal degradation (Dephoure et al, 2014; McShane et al, 2016; Santaguida et al, 2015; Stingele et al, 2012; Torres et al, 2010). The energetic cost of expressing, folding, and turning over excess proteins, as well as the downstream consequences of unmitigated protein imbalances, impose a significant fitness cost on the cell.…”

Section: Discussionmentioning

confidence: 99%

Single-chromosome Gains Commonly Function as Tumor Suppressors

et al. 2017

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SUMMARY Aneuploidy is a hallmark of cancer, although its effects on tumorigenesis are unclear. Here, we investigated the relationship between aneuploidy and cancer development using cells engineered to harbor single extra chromosomes. We found that nearly all trisomic cell lines grew poorly in vitro and as xenografts, relative to genetically matched euploid cells. Moreover, the activation of several oncogenic pathways failed to alleviate the fitness defect induced by aneuploidy. However, following prolonged growth, trisomic cells acquired additional chromosomal alterations that were largely absent from their euploid counterparts and that correlated with improved fitness. Thus, while single-chromosome gains can suppress transformation, the genome-destabilizing effects of aneuploidy confer an evolutionary flexibility that may contribute to the aggressive growth of advanced malignancies with complex karyotypes.

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Section: Discussionmentioning

confidence: 99%

Single-chromosome Gains Commonly Function as Tumor Suppressors

et al. 2017

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“…The subsequent formation of an X-β-gal homotetramer led to the nearly (but not quite) complete cessation of the degradation of a "mature" X-β-gal tetramer by the Arg/N-end rule pathway (15,18,19). Later studies have shown that a non-first-order degradation kinetics is also a frequent aspect of proteolysis by the Ub system at large, resulting, primarily, from the same causes of time-dependent protein folding and formation of protein complexes (44,(57)(58)(59).…”

Section: Degradation Of Chk1 In Naa10δ Cells Does Not Involve the Cup9mentioning

confidence: 99%

Control of Hsp90 chaperone and its clients by N-terminal acetylation and the N-end rule pathway

Hyun

Varshavsky

2017

Proc. Natl. Acad. Sci. U.S.A.

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We found that the heat shock protein 90 (Hsp90) chaperone system of the yeast Saccharomyces cerevisiae is greatly impaired in naa10Δ cells, which lack the NatA N α -terminal acetylase (Nt-acetylase) and therefore cannot N-terminally acetylate a majority of normally N-terminally acetylated proteins, including Hsp90 and most of its cochaperones. Chk1, a mitotic checkpoint kinase and a client of Hsp90, was degraded relatively slowly in wild-type cells but was rapidly destroyed in naa10Δ cells by the Arg/N-end rule pathway, which recognized a C terminus-proximal degron of Chk1. Diverse proteins (in addition to Chk1) that are shown here to be targeted for degradation by the Arg/N-end rule pathway in naa10Δ cells include Kar4, Tup1, Gpd1, Ste11, and also, remarkably, the main Hsp90 chaperone (Hsc82) itself. Protection of Chk1 by Hsp90 could be overridden not only by ablation of the NatA Nt-acetylase but also by overexpression of the Arg/N-end rule pathway in wild-type cells. Split ubiquitin-binding assays detected interactions between Hsp90 and Chk1 in wild-type cells but not in naa10Δ cells. These and related results revealed a major role of Nt-acetylation in the Hsp90-mediated protein homeostasis, a strong up-regulation of the Arg/N-end rule pathway in the absence of NatA, and showed that a number of Hsp90 clients are previously unknown substrates of the Arg/N-end rule pathway.roteins called chaperones promote the in vivo protein folding and counteract misfolding, maladaptive protein aggregation, and other perturbations of proteostasis (1-4). Hsp90 is an ATPdependent chaperone system that mediates the conformational maturation and stabilization of many proteins. Referred to as Hsp90 clients, these proteins include kinases, transcriptional regulators, and many other proteins that comprise at least 20% of a cellular proteome. The diversity of Hsp90 clients and the broad range of processes that involve Hsp90 underlie its necessity for cell viability in all eukaryotes (5-11). Cochaperones of the ∼90-kDa Hsp90 comprise, in mammals, ∼30 distinct proteins. They participate in the delivery of clients to Hsp90 and contribute to related processes, including ATP hydrolysis by Hsp90 (12). Because of its ability to modulate protein conformations, the Hsp90 system can either exacerbate or counteract the fitness-reducing effects of mutations in cellular proteins. This property of Hsp90 affects the standing genetic variation and thereby influences the impact of natural selection on rates and directions of evolution (13,14).The N-end rule pathways comprise a set of proteolytic systems whose unifying feature is their ability to recognize proteins containing N-terminal (Nt) degradation signals called N-degrons, thereby causing the degradation of these proteins by the proteasome or autophagy in eukaryotes and by the proteasome-like ClpAP protease in bacteria (Fig. 1) (15-26). The main determinant of an N-degron is a destabilizing Nt-residue of a protein. Many N-degrons become active through their enzymatic Nt-acetylation, Ntformylation...

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“…In vivo half-lives of intracellular proteins range from less than a minute to many days (1)(2)(3)(4)(5)(6). The term "half-life" is, at best, an approximate descriptor of a protein's degradation curve.…”

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confidence: 99%

“…(ii) The process of conformational maturation, i.e., transitions from a newly formed, still partially unfolded (and often more vulnerable to proteolysis) monomer of a protein to its final state, either as a folded monomer or an oligomer of the homo or hetero kind. Mature proteins are usually more resistant to proteolysis, in part through steric shielding of their degradation signals (degrons) (4,5,(13)(14)(15)(16)(17)(18)(19). (iii) A variety of chemical (usually enzymatic) modifications of a protein that can change its metabolic stability either cotranslationally or posttranslationally.…”

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confidence: 99%