Understanding diversity in telomere dynamics

Monaghan, Pat; Eisenberg, Dan T. A.; Harrington, Lea; Nussey, Dan

doi:10.1098/rstb.2016.0435

Cited by 54 publications

(44 citation statements)

References 38 publications

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“…These types of regulations on TERT through alternative splicing also are consistent with Peto’s paradox [33]. The investment into regulatory mechanisms of critical genes, such as TERT, ensures somatic maintenance and allows for larger, long-lived mammals to have lower cancer incidence even though they are made up of more cells that divide over longer periods of time than their smaller, short-lived counterparts [32, 34]. The cis element DR8 has a critical role in this regulation.…”

Section: Discussionmentioning

confidence: 68%

NOVA1 directs PTBP1 to hTERT pre-mRNA and promotes telomerase activity in cancer cells

et al. 2018

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Alternative splicing is dysregulated in cancer cells, driving the production of isoforms that allow tumor cells to survive and continuously proliferate. Part of the reactivation of telomerase involves the splicing of hTERT transcripts to produce full-length (FL) TERT . Very few splicing factors to date have been described to interact with hTERT and promote the production of FL TERT . We recently described one such splicing factor, NOVA1, that acts as an enhancer of FL hTERT splicing, increases telomerase activity, and promotes telomere maintenance in cancer cells. NOVA1 is expressed primarily in neurons and is involved in neurogenesis. In the present studies, we describe that polypyrimidine-tract binding proteins (PTBPs), which are also typically involved in neurogenesis, are also participating in the splicing of hTERT to FL in cancer. Knockdown experiments of PTBP1 in cancer cells indicate that PTBP1 reduces hTERT FL splicing and telomerase activity. Stable knockdown of PTBP1 results in progressively shortened telomere length in H1299 and H920 lung cancer cells. RNA pulldown experiments reveal that PTBP1 interacts with hTERT pre-mRNA in a NOVA1 dependent fashion. Knockdown of PTBP1 increases the expression of PTBP2 which also interacts with NOVA1, potentially preventing the association of NOVA1 with hTERT pre-mRNA. These new data highlight that splicing in cancer cells is regulated by competition for splice sites and that combinations of splicing factors interact at cis regulatory sites on pre-mRNA transcripts. By employing hTERT as a model gene, we show the coordination of the splicing factors NOVA1 and PTBP1 in cancer by regulating telomerase that is expressed in the vast majority of cancer cell types.

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Section: Discussionmentioning

confidence: 68%

NOVA1 directs PTBP1 to hTERT pre-mRNA and promotes telomerase activity in cancer cells

et al. 2018

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“…In contrast, while the number of studies investigating telomeres (i.e. telomere length and dynamics) in non‐human animals have substantially increased in the last decade (reviewed in Haussmann & Marchetto ; Monaghan ; Bateson ; Reichert & Stier ; Angelier et al ; Monaghan et al ), general conclusions about stress‐induced telomere dynamics are lacking due to the paucity of comparative studies that would quantify the effect size of the association between the exposure to potential stressors and telomere length and dynamics.…”

Section: Introductionmentioning

confidence: 99%

The association between stressors and telomeres in non‐human vertebrates: a meta‐analysis

2019

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Animal response to stressors such as harsh environmental conditions and demanding biological processes requires energy generated through increased mitochondrial activity. This results in the production of reactive oxygen species (ROS). In vitro and some in vivo studies suggest that oxidative damage of DNA caused by ROS is responsible for telomere shortening. Since telomere length is correlated with survival in many vertebrates, telomere loss is hypothesised to trigger cellular ageing and/ or to reflect the harshness of the environment an individual has experienced. To improve our understanding of stress‐induced telomere dynamics in non‐human vertebrates, we analysed 109 relevant studies in a meta‐analytical framework. Overall, the exposure to possible stressors was associated with shorter telomeres or higher telomere shortening rate (average effect size = −0.16 ± 0.03). This relationship was consistent for all phylogenetic classes and for all a priori‐selected stressor categories. It was stronger in the case of pathogen infection, competition, reproductive effort and high activity level, which emphasises their importance in explaining intraspecific telomere length variability and, potentially, lifespan variability. Interestingly, the association between stressor exposure and telomeres in one hand, and oxidative stress in the other hand, covaried, suggesting the implication of oxidative stress in telomere dynamics.

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“…Barnes, Fouquerel, & Opresko, 2019;Chatelain, Drobniak, & Szulkin, 2020;Epel et al, 2004;Kotrschal, Ilmonen, & Penn, 2007;Reichert & Stier, 2017), which in turn may increase aging rate and hence shortening life span (Heidinger et al, 2012;Wilbourn et al, 2018). Despite the increasing interest in studying telomere dynamics (Monaghan, Eisenberg, Harrington, & Nussey, 2018), the effect of environmental stress on telomere attrition in ectotherms is still largely unknown (Angelier, Costantini, Blévin, & Chastel, 2018;Chatelain et al, 2020;Olsson et al, 2018). One reason why understanding telomere dynamics is often difficult is that maternal effects are known to affect offspring phenotype including offspring telomere length (Asghar, Bensch, Tarka, Hansson, & Hasselquist, 2015;Haussmann & Heidinger, 2015;Marasco, Boner, Griffiths, Heidinger, & Monaghan, 2019) which, along with environmental stressors, determines the subsequent telomere dynamic in the adulthood (Heidinger et al, 2012).…”

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confidence: 99%

Maternal predator‐exposure affects offspring size at birth but not telomere length in a live‐bearing fish

Monteforte

Cattelan

Morosinotto

et al. 2020

Ecology and Evolution

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The perception of predation risk could affect prey phenotype both within and between generations (via parental effects). The response to predation risk could involve modifications in physiology, morphology, and behavior and can ultimately affect long‐term fitness. Among the possible modifications mediated by the exposure to predation risk, telomere length could be a proxy for investigating the response to predation risk both within and between generations, as telomeres can be significantly affected by environmental stress. Maternal exposure to the perception of predation risk can affect a variety of offspring traits but the effect on offspring telomere length has never been experimentally tested. Using a live‐bearing fish, the guppy (Poecilia reticulata), we tested if the perceived risk of predation could affect the telomere length of adult females directly and that of their offspring with a balanced experimental setup that allowed us to control for both maternal and paternal contribution. We exposed female guppies to the perception of predation risk during gestation using a combination of both visual and chemical cues and we then measured female telomere length after the exposure period. Maternal effects mediated by the exposure to predation risk were measured on offspring telomere length and body size at birth. Contrary to our predictions, we did not find a significant effect of predation‐exposure neither on female nor on offspring telomere length, but females exposed to predation risk produced smaller offspring at birth. We discuss the possible explanations for our findings and advocate for further research on telomere dynamics in ectotherms.

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Understanding diversity in telomere dynamics

Cited by 54 publications

References 38 publications

NOVA1 directs PTBP1 to hTERT pre-mRNA and promotes telomerase activity in cancer cells

NOVA1 directs PTBP1 to hTERT pre-mRNA and promotes telomerase activity in cancer cells

The association between stressors and telomeres in non‐human vertebrates: a meta‐analysis

Maternal predator‐exposure affects offspring size at birth but not telomere length in a live‐bearing fish

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