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Transcriptional outcome of telomere signalling

Nature Reviews Genetics volume 15, pages 491–503 (2014)Cite this article

Subjects

Key Points

  • Telomeres protect chromosome ends from unwanted activation of DNA damage response and hazardous replication by a complex and specific network of interactions among DNA, RNA (telomere repeat-containing RNAs), enzymes (telomerase) and specialized proteins (the shelterin complex), as well as general chromatin and repair factors.

  • Specialized telomeric factors such as shelterin components and telomerase can be found outside telomeres, where they have different roles in transcriptional regulation.

  • In budding yeast, delocalization of the telomeric protein Rap1 from critically short telomeres contributes to the transcriptomic changes seen in senescent cells.

  • In mammals, the shelterin subunit RAP1 regulates the expression of gene networks that are related to metabolism and immunity. The shelterin subunit TRF2 regulates neuronal gene expression networks, and telomerase is involved in the transcription of a subset of Wnt/β-catenin and NF-κB target genes.

  • Three non-exclusive mechanisms can be envisaged to explain how telomeres signal their changes through the regulation of the transcriptional properties of their constituents: post-translational modifications, looping and subnuclear compartmentalization.

  • As each telomeric protein may control specific gene networks, the consequences of telomere dysfunction might be more tissue specific than previously expected. Blocking the extratelomeric functions of telomeric proteins should be considered a viable option for drugs against cancer and age-related pathologies without secondary effects due to telomere uncapping.

Abstract

Telomeres protect chromosome ends from degradation and inappropriate DNA damage response activation through their association with specific factors. Interestingly, these telomeric factors are able to localize outside telomeric regions, where they can regulate the transcription of genes involved in metabolism, immunity and differentiation. These findings delineate a signalling pathway by which telomeric changes control the ability of their associated factors to regulate transcription. This mechanism is expected to enable a greater diversity of cellular responses that are adapted to specific cell types and telomeric changes, and may therefore represent a pivotal aspect of development, ageing and telomere-mediated diseases.

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Figure 1: Telomere organization and signalling.
Figure 2: Subnuclear distribution of telomeric factors has a role in the transcriptional patterns of senescent yeast.
Figure 3: Extratelomeric binding of mammalian RAP1 and TRF2.
Figure 4: Extratelomeric roles of shelterin components in transcriptional control.
Figure 5: Coordination of telomeric state with transcriptional regulation.
Figure 6: Model of telomere signalling that links DDR activation and transcriptional regulation by telomeric proteins.

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Acknowledgements

The authors thank the discussions and suggestions of all the members of the E.G. team, as well as M. Shkreli, V. Géli, P. Lopez and E. van Obberghen. They are also grateful to the anonymous reviewers for helpful suggestions. The E.G. team is supported by La Ligue Nationale contre le Cancer ('Equipe labellisée'), the French Institut National du Cancer (programmes TELOFUN and TELOCHROM), the French National Research Agency (ANR) (programmes TELOREP and INNATELO) and the Investments for the Future LABEX SIGNALIFE (programme reference # ANR-11-LABX-0028-01). They apologize for all the important works that have not been cited owing to space limitation.

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Authors and Affiliations

  1. Emergency Department, Pôle Sino-Français de Recherches en Sciences du Vivant et Génomique, Shanghai Ruijin Hospital, Shanghai, 200025, China

    Jing Ye

  2. Institute for Research on Cancer and Aging, Nice (IRCAN), Nice University, CNRS UMR7284/INSERM U1081, Faculty of Medicine, 06107, Nice, France

    Valérie M. Renault, Karine Jamet & Eric Gilson

  3. Department of Medical Genetics, Hopital de l'Archet 2, CHU de Nice, BP 3079, Nice cedex 3, 06202, France

    Eric Gilson

  4. Pôle Sino-Français de Recherches en Sciences du Vivant et Génomique, Shanghai Ruijin Hospital, Shanghai, 200025, China

    Eric Gilson

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  1. Jing Ye
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Correspondence to Eric Gilson.

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DNA damage response

(DDR). A pathway triggered by DNA lesions, in which phosphatidylinositol-3 kinases (ATM, ATR or DNA-PK) activate appropriate repair pathways and/or cell cycle arrest.

Senescence

A permanent arrest in the cell cycle.

Apoptosis

A form of programmed cell death.

Extracellular stress response pathways

Pathways that are triggered by extracellular stimuli and that involve mitogen-activated protein kinases such as JNK and p38 to activate an adaptive response programme, which maximizes cell cycle progression and survival.

NF-κB signalling

A pathway mediated by nuclear factor-κB (NF-κB) that regulates many physiological processes, including innate and adaptive immune responses, cell death and inflammation.

Mass action law

A mathematical model based on the principle that the rate of a chemical reaction is proportional to the molecular concentrations of the reacting substances.

Wnt/β-catenin signalling

A fundamental and complex pathway that is required for metazoan development and tissue homeostasis; it is often dysregulated in cancer.

Luciferase reporter assays

Assays commonly used to assess the transcriptional activity in cells that are transfected with a genetic construct containing the luciferase gene under the control of a promoter of interest.

Glucose intolerance

A metabolic disorder associated with insulin resistance, which is considered to be a pre-diabetic state.

Hepatic steatosis

The accumulation of stored lipids — most notably, triglycerides — to abnormally high levels in the liver.

Oxidative phosphorylation

A metabolic pathway in which the mitochondria use energy released by the oxidation of nutrients to generate ATP.

White fat

Adipose tissue used as energy storage.

Poly(ADP-ribose) polymerases

A family of proteins involved in various cellular processes, including DNA repair, regulation of chromatin structure and regulation of cell cycle checkpoints.

E3 ubiquitin ligase

An enzyme that couples the small (7 kDa) protein ubiquitin to lysine residues on proteins targeted for degradation by the proteasome.

Natural killer cells

Cytotoxic cells that are crucial for eliminating infected, damaged or cancerous cells.

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Ye, J., Renault, V., Jamet, K. et al. Transcriptional outcome of telomere signalling. Nat Rev Genet 15, 491–503 (2014). https://doi.org/10.1038/nrg3743

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