A two-step model for senescence triggered by a single critically short telomere

Abdallah, Pauline; Luciano, Pierre; Runge, Kurt W.; Lisby, Michael; Géli, Vincent; Gilson, Éric; Teixeira, Maria Teresa

doi:10.1038/ncb1911

Cited by 157 publications

(231 citation statements)

References 35 publications

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“…2A, plate YPD(40 G)). This latter pattern is reminiscent of that seen in senescing WT cultures after telomerase loss (10,35,36) (Fig. 2A, plate YPD(60 G)).…”

Section: Telomerase Loss In Yeast With Vertebrate-type Telomeressupporting

confidence: 54%

Telomerase Is Required to Protect Chromosomes with Vertebrate-type T2AG3 3′ Ends in Saccharomyces cerevisiae

Bah

Gilson

Wellinger

2011

Journal of Biological Chemistry

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Telomeres containing vertebrate-type DNA repeats can be stably maintained in Saccharomyces cerevisiae cells. We show here that telomerase is required for growth of yeast cells containing these vertebrate-type telomeres. When present at the chromosome termini, these heterologous repeats elicit a DNA damage response and a certain deprotection of telomeres. The data also show that these phenotypes are due only to the terminal localization of the vertebrate repeats because if they are sandwiched between native yeast repeats, no phenotype is observed. Indeed and quite surprisingly, in this latter situation, telomeres are of virtually normal lengths, despite the presence of up to 50% of heterologous repeats. Furthermore, the presence of the distal vertebrate-type repeats can cause increased problems of the replication fork. These results show that in budding yeast the integrity of the 3 overhang is required for proper termination of telomere replication as well as protection.Specialized ribonucleoprotein complexes known as telomeres protect the natural ends of eukaryotic chromosomes. In the budding yeast Saccharomyces cerevisiae, telomeres are composed of an ϳ300-bp double-stranded (ds) 4 tract of irregular repeats, abbreviated TG 1-3 /C 1-3 A, and terminate with a 12-to 14-nt single-stranded (ss) 3Ј overhang made of the TG 1-3 motifs (1-3). In contrast, vertebrate telomeres contain a ds tract containing thousands of T 2 AG 3 /C 3 TA 2 repeats and terminate with a ss 3Ј overhang made of T 2 AG 3 motifs (2, 4, 5).The complete replication of linear eukaryotic chromosomes requires the de novo addition of telomeric repeats to chromosome ends by telomerase, a specialized reverse transcriptase (for reviews, see Refs. 6 -9). The core telomerase components are a reverse-transcriptase catalytic subunit and a RNA moiety. In yeast, these components are known as Est2p and TLC1, respectively (8). The telomerase RNA always contains a short region that is complementary to the G-rich strand of telomeric repeats, and that region is used as a template for repeat addition (7, 9).Telomerase invalidation leads to gradual telomere shortening and ultimately causes cells to stop dividing (7, 9, 10). Nevertheless, cellular backup mechanisms can maintain telomeres in the absence of telomerase and ultimately preserve genome integrity. In this mode of telomere maintenance, which is known as alternative lengthening of telomeres in human cells, and survivor mode in Saccharomyces cerevisiae, telomeric DNA is maintained via homologous recombination-based mechanisms (11,12).By differentiating chromosomal ends from internal ds breaks, telomeres also prevent chromosomal ends from eliciting DNA damage checkpoint activation and protect telomeres from inappropriate DNA repair activity. Binding of the multiprotein complex shelterin is essential for both protecting and maintaining the length of mammalian telomeres (13,14). Rap1p, one of the several proteins associated with similar functions at budding yeast telomeres, binds directly to ds telomeric repeats ...

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“…2A, plate YPD(40 G)). This latter pattern is reminiscent of that seen in senescing WT cultures after telomerase loss (10,35,36) (Fig. 2A, plate YPD(60 G)).…”

Section: Telomerase Loss In Yeast With Vertebrate-type Telomeressupporting

confidence: 54%

Telomerase Is Required to Protect Chromosomes with Vertebrate-type T2AG3 3′ Ends in Saccharomyces cerevisiae

Bah

Gilson

Wellinger

2011

Journal of Biological Chemistry

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“…To further demonstrate breast cancer cell senescence, we measured telomerase activity and telomere length, as the reduction of both are among the key molecular events underpinning the permanent cell cycle arrest of cancer cell senescence (30,31). In cultured cells expressing GFP-GAPDH, there was a significant inhibition of telomerase activity and shortening of telomere length, compared with that in cell cultures expressing GFP alone ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) induces cancer cell senescence by interacting with telomerase RNA component

Nicholls

Pinto

et al. 2012

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

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Oxidative stress regulates telomere homeostasis and cellular aging by unclear mechanisms. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is a key mediator of many oxidative stress responses, involving GAPDH nuclear translocation and induction of cell death. We report here that GAPDH interacts with the telomerase RNA component (TERC), inhibits telomerase activity, and induces telomere shortening and breast cancer cell senescence. The Rossmann fold containing NAD + binding region on GAPDH is responsible for the interaction with TERC, whereas a lysine residue in the GAPDH catalytic domain is required for inhibiting telomerase activity and disrupting telomere maintenance. Furthermore, the GAPDH substrate glyceraldehyde-3-phosphate (G3P) and the nitric oxide donor S-nitrosoglutathione (GSNO) both negatively regulate GAPDH inhibition of telomerase activity. Thus, we demonstrate that GAPDH is regulated to target the telomerase complex, resulting in an arrest of telomere maintenance and cancer cell proliferation. and apoptosis. Although production of daughter cells costs energy, it remains largely elusive how energy metabolism regulates normal cell aging and lifespan. Considerable evidence suggests that metabolic waste causes premature senescence and apoptosis, shortening cellular lifespan. Accumulation of reactive oxygen species (ROS) damages cellular enzymes, organelle membranes, and chromosomal DNA including telomeres (the ends of chromosomes) (1, 2). Whereas enzymes that reduce the production of metabolic hazards may operate to extend cellular lifespan, recent studies demonstrate that the energy producing enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) that limits ROS production undergoes structural modifications and travel into the nucleus (3-7) to interact with telomeres directly and to potentially alleviate stress-induced cell aging (8, 9).Human telomeres are composed of arrays of a few thousand tandem DNA repeats of TTAGGG and various binding proteins. Telomeres undergo progressive shortening as somatic cells divide, due to the inability of cells to replicate the extreme ends of chromosomes. When telomeres are critically short, cells exit the cell cycle and undergo cell senescence (10-13). As a measure to maintain telomeres for continuous renewal of germ lines, development of embryonic stem cells, clonal expansion of lymphocytes, and immortalization of neoplastic cells, telomerase is activated to synthesize and maintain telomeres by reverse transcription (10-13).Telomerase is a large ribonucleoprotein complex containing the catalytic subunit telomerase reverse transcriptase (TERT) and an RNA template (reviewed in refs. 13 and 14). Human telomerase reverse transcriptase (hTERT) comprises 1,132 amino acid residues and human telomerase RNA (hTERC) is composed of 451 nucleotides (15-18). Reconstitution of telomerase activity in telomerase-negative cells can be achieved by expression of hTERT, demonstrating that hTERT is the rate-limiting component of the enzyme complex (19,20).GAPDH has long been recognize...

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“…Importantly, Slx5/Slx8 mutants are impaired or delayed for the generation of type II survivors [61], in which telomeric TG repeats are maintained by a Rad51-independent recombination pathway in the absence of telomerase [62]. From these data we propose a model which suggests that a critically short telomere, generated by the loss of telomerase activity or collapse of replication forks, can be recognized as damage [60,63] and be transferred to nuclear pores, where Slx5/Slx8-mediated ubiquitylation and degradation of a target protein facilitates alternative telomere elongation. What this target is remains unknown.…”

Section: Nuclear Envelope and Genome Stability: Sumo Connectionsmentioning

confidence: 96%

“…Peripheral tethering possibly limits the access of the telomeric repeats to the recombinational machinery mediating sister chromatid exchange, which was shown to be enriched in the nuclear interior [67]. involved in checkpoint kinase recruitment and recombination, notably Cdc13, RPA and Rad52 [59,60]. Importantly, Slx5/Slx8 mutants are impaired or delayed for the generation of type II survivors [61], in which telomeric TG repeats are maintained by a Rad51-independent recombination pathway in the absence of telomerase [62].…”

Section: Nuclear Envelope and Genome Stability: Sumo Connectionsmentioning

confidence: 99%

Nuclear organization in genome stability: SUMO connections

2011

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Recent findings show that chromatin dynamics and nuclear organization are not only important for gene regulation and DNA replication, but also for the maintenance of genome stability. In yeast, nuclear pores play a role in the maintenance of genome stability by means of the evolutionarily conserved family of SUMO-targeted Ubiquitin ligases (STUbLs). The yeast Slx5/Slx8 STUbL associates with a class of DNA breaks that are shifted to nuclear pores. Functionally Slx5/Slx8 are needed for telomere maintenance by an unusual recombination-mediated pathway. The mammalian STUbL RNF4 associates with Promyelocytic leukaemia (PML) nuclear bodies and regulates PML/PMLfusion protein stability in response to arsenic-induced stress. A subclass of PML bodies support telomere maintenance by the ALT pathway in telomerase-deficient tumors. Perturbation of nuclear organization through either loss of pore subunits in yeast, or PML body perturbation in man, can lead to gene amplifications, deletions, translocations or endto-end telomere fusion events, thus implicating SUMO and STUbLs in the subnuclear organization of select repair events.

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A two-step model for senescence triggered by a single critically short telomere

Cited by 157 publications

References 35 publications

Telomerase Is Required to Protect Chromosomes with Vertebrate-type T2AG3 3′ Ends in Saccharomyces cerevisiae

Telomerase Is Required to Protect Chromosomes with Vertebrate-type T2AG3 3′ Ends in Saccharomyces cerevisiae

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) induces cancer cell senescence by interacting with telomerase RNA component

Nuclear organization in genome stability: SUMO connections

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