Telomere Biology and Cancer Mechanisms

Telomeres are specialised nucleoprotein structures capping eukaryotic chromosomes, maintaining genomic stability by preventing end-to-end fusions and unrecognised DNA damage responses. In normal somatic cells, progressive telomere attrition triggers replicative senescence, a key tumour-suppressive barrier. Cancer cells bypass this barrier predominantly by reactivating telomerase, a ribonucleoprotein reverse transcriptase that rebuilds telomeric repeats. A subset of tumours employs an alternative lengthening of telomeres (ALT) pathway, driven by homologous recombination and chromatin alterations. Recent studies have delineated intricate regulatory networks involving shelterin components, telomeric-repeat-containing RNA (TERRA) and chromatin remodellers such as ATRX-DAXX. Genomic alterations, including TERT promoter mutations, amplify telomerase expression, contributing to cellular immortalisation. Understanding these mechanisms is central to novel biomarker development and targeted therapies that aim to destabilise telomere maintenance in cancer cells.

Research from Nature Portfolio

Recent work has uncovered an innate immune signalling axis linking dysfunctional telomeres to mitochondrial antiviral pathways. A telomere-associated isoform of the DNA sensor ZBP1 is activated by telomeric RNA transcripts (TERRA) and oligomerises on mitochondria to engage MAVS, driving a tumour-suppressive crisis programme in cells with critically short telomeres. Studies of the ALT pathway have revealed a pivotal role for RNaseH1 in regulating RNA–DNA hybrids at telomeres; fine-tuning of these hybrids is essential to stimulate recombination without catastrophic telomere loss. Complementary research has shown that reintroduction of the chromatin remodeller ATRX suppresses ALT by resolving G-quadruplex DNA structures, reducing replication fork stalling and limiting homologous recombination at telomeres.

Telomere Biology and Cancer Mechanisms publication trend

The graph below shows the total number of articles in telomere biology and cancer mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Telomere: Tandem nucleotide repeat region at chromosomal ends that protects genomic DNA from degradation and fusion.

Telomerase: Ribonucleoprotein enzyme that extends telomeric repeats using an intrinsic RNA template.

Replicative senescence: Permanent cell cycle arrest triggered by critically short telomeres.

Alternative lengthening of telomeres (ALT): Telomerase-independent telomere extension mechanism relying on homologous recombination.

TERRA: Telomeric-repeat-containing RNA transcripts involved in telomere regulation and DNA damage signalling.

G-quadruplex: Four-stranded DNA secondary structure formed by guanine-rich telomeric sequences.

References

1. Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis. Nature (2023).
2. RNaseH1 regulates TERRA-telomeric DNA hybrids and telomere maintenance in ALT tumour cells. Nature Communications (2014).
3. Suppression of the alternative lengthening of telomere pathway by the chromatin remodelling factor ATRX. Nature Communications (2015).
4. Telomere position effect: regulation of gene expression with progressive telomere shortening over long distances. Genes & Development (2014).
5. Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies. Genome Medicine (2016).
6. Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: old actors and new players. Oncogene (2019).