Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins

Key Points

  • Mammalian telomeres are formed by tandem repeats of the TTAGGG sequence bound by a specialized six-protein complex known as shelterin, which has fundamental roles in the protection of chromosomes and the regulation of telomerase activity at chromosome ends. Excessive telomere shortening and severe telomere uncapping trigger a DNA damage response at chromosome ends, which are then recognized as double-strand breaks. Dysfunctional telomeres can lead to either cancer or ageing pathologies depending on the integrity of the DNA damage response. Studies with mouse models that support a role for these proteins in cancer susceptibility and ageing-related pathologies are discussed in this Review.

  • Telomere dysfunction causes ageing and also constitutes a driving force for cellular transformation by causing genome instability. Molecular mechanisms underlying telomere-induced genomic instability are described.

  • Anti-ageing activity of telomerase has been demonstrated in mice overexpressing TERT genetically engineered to be cancer-resistant by means of enhanced expression of the p53, p16 and ARF tumour suppressors. Telomere-maintenance is the main mechanism underlying the anti-ageing phenotype of TERT-transgenic mice.

  • Telomere-independent functions of TERT have recently been described. Overexpression of TERT is a transcriptional modulator of the Wnt–β-catenin signalling pathway and has RNA-dependent RNA polymerase activity when in a complex with the RNA component of mitochondrial RNA processing endoribonuclease (RMRP).

  • Roles for the shelterin component RAP1 beyond its roles in telomeres have been uncovered. Mammalian RAP1 is involved in subtelomeric gene silencing and transcriptional regulation, and it also acts as a essential modulator of the nuclear factor-κB (NF-κB)-mediated pathway.

  • Telomerase and factors that influence its activity are very attractive targets for the treatment of degenerative diseases and cancer. TPP1 is involved in telomerase recruitment to telomeres. Drugs targeting TPP1 could certainly be a novel strategy for blocking the ultimate goal of telomerase, the lengthening of telomeres.

Abstract

Mammalian telomeres are formed by tandem repeats of the TTAGGG sequence, which are progressively lost with each round of cell division. Telomere protection requires a minimal length of TTAGGG repeats to allow the binding of shelterin, which prevents the activation of a DNA damage response (DDR) at chromosome ends. Telomere elongation is carried out by telomerase. Telomerase can also act as a transcriptional modulator of the Wnt–β-catenin signalling pathway and has RNA-dependent RNA polymerase activity. Dysfunctional telomeres can lead to either cancer or ageing pathologies depending on the integrity of the DDR. This Review discusses the role of telomeric proteins in cancer and ageing through modulating telomere length and protection, as well as regulating gene expression by binding to non-telomeric sites.

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Figure 1: Telomere structure and functional roles of the telomeric proteins.
Figure 2: Telomere dysfunction as a driver of genomic instability.
Figure 3: RAP1 telomeric and extra-telomeric roles.
Figure 4: Telomerase, a master in coping with multiple jobs.

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Acknowledgements

P.M. is a 'Ramón y Cajal' senior scientist. M.A.B.'s laboratory is funded by the Spanish Ministry of Innovation and Science, the European Union (géenica, FP7), the European Reseach Council (ERC Advance Grants), the Spanish Association Against Cancer (AECC) and the Körber European Science Award. The authors apologize to all authors whose work has not been cited owing to space limitations.

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Glossary

Telomere uncapping

Loss of proper telomere structure owing to either loss of telomeric repeat sequences or alteration in telomere proteins that leads to the activation of the DNA damage response.

Mismatch repair pathway

DNA repair mechanism that corrects mispaired nucleotides that originate during DNA replication and recombination.

Oral leukoplakia

The most common premalignant or potentially malignant disorder of the oral mucosa characterized by presenting several degrees of epithelia dysplasia. Defined as a white patch or plaque of the oral mucosa that cannot be characterized clinically or pathologically as any other disease.

Chromatid dicentrics

Aberrant dicentric chromosome that results when a chromosome lacking a telomere or with a dysfunctional telomere replicates and its sister chromatids fuse at their ends. At anaphase, the fused sister chromatids break owing to the presence of two centromeres.

Dicentric chromosome

Chromosome with two centromeres that results from the fusion of two monocentric chromosome pieces.

Multicentric chromosome

Chromosome with multiple centromeres that results from the fusion of several chromosome pieces.

Ring

Aberrant monocentric chromosome the arms of which have fused together to form a ring.

Double-minute chromosome

Acentric chromatin circle of variable size that consists of multiple copies of a short rearranged DNA segment that has undergone amplification.

G-quadruplex

Four-stranded structure formed by nucleic acids rich in guanine that consists of a square arrangement of guanines stabilized by Hoogsteen hydrogen bonds. Can form within or between G-rich strands of telomeric DNA.

Fragile site

Genomic region prone to replication fork stalling in which gaps and breaks frequently occur and is thus a hotspot for recombination events.

Multiple telomeric signal (MTS)

An aberrant structure at telomeres that is enhanced by conditions known to cause replication fork collapse, such as aphidicolin treatment. By immunofluorescence technique, an MTS is seen as several fluorescent dots instead of just one.

Hypomorphic mutation

A type of mutation that results in an altered gene product with reduced enzymatic activity or a lower expression level than the wild-type allele.

Chromosome concatenation

Aberrant chromosomal structure in which several chromosomes are fused.

Cyclobutane pyrimidine dimer (CPD)

Interstrand DNA lesion formed when two adjacent pyrimidines are joined across their 5–6 double bonds owing to the UV radiation excitation of one of the pyrimidines.

Nucleotide excision repair (NER)

DNA repair mechanism that removes UV radiation-induced helix-distorting lesions such as pyrimidine dimers and 6,4 photoproducts. Two subpathways exist: global genomic NER and transcription-coupled NER.

Xeroderma pigmentosum

Autosomal recessive genetic disorder linked to mutations in components within the NER pathway. Patients are deficient in repairing UV radiation-induced DNA damage and are prone to develop skin cancers and several skin malignancies such as keratoses, hyperpigmentation and blistering.

Spindle assembly checkpoint (SAC)

Monitors proper chromosome attachment to spindle microtubules. SCA prevents anaphase until all chromosomes are properly attached to the spindle. To achieve proper segregation, the two kinetochores on the sister chromatids must be attached to opposite spindle poles. It is composed of mitotic checkpoint proteins MAD and BUB. These reside on kinetochores and show changes in phosphorylation and localization as cells proceed through mitosis. Failure of SAC can result in aneuploidy.

Gene set enrichment analysis (GSEA)

A computational method that determines whether an a priori defined set of genes shows significant differences between two biological states.

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Martínez, P., Blasco, M. Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins. Nat Rev Cancer 11, 161–176 (2011). https://doi.org/10.1038/nrc3025

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