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Telomere maintenance as a target for anticancer drug discovery

Nature Reviews Drug Discovery volume 1, pages 383–393 (2002)Cite this article

Key Points

  • The ends of the chromosomes in all eukaryotic species have specialized, non-coding DNA sequences that, together with associated proteins, are known as telomeres. These have developed to protect the chromosome ends from a range of otherwise catastrophic events.

  • Telomeric DNA comprises simple tandem repeats of guanine-rich sequences, typified by the hexanucleotide repeat d(TTAGGG)n in vertebrates. The extreme 3′ end of eukaryotic telomeric DNA is single-stranded, typically being 100–200 bases long.

  • In normal cells, telomeres progressively decrease in length with each successive round of cell division owing to the inability of endogenous DNA polymerase to fully replicate the lagging telomeric DNA strand. Once a critical level of telomere shortening is reached, cells enter an irreversible phase of growth arrest, when they cease to divide and might then be directed to apoptotic cell death.

  • In striking contrast, telomeres of cancer cells do not shorten on replication, but remain constant in length on succeeding generations owing to the activity of the enzyme telomerase, an RNA-dependent DNA polymerase that uses its own associated RNA template to catalyse the addition of telomeric DNA repeats to the 3′ end of the single-stranded DNA telomere.

  • Telomerase is not expressed in normal human tissue, but is present in at least 80–85% of tumour cells, suggesting it might be both a diagnostic marker and a target for the design of broad-spectrum anti-cancer drugs. Proof-of-principle experiments have shown that telomerase inhibition leads to telomere length reduction, tumour-cell senescence and ultimately apoptosis.

  • Three approaches to telomerase inhibition are the subject of current investigation: targeting the active site of the polymerase with small molecules; antisense oligonucleotides directed at the RNA template; and stabilization of the single-stranded telomeric DNA into quadruplex structures formed from stacked guanine quartets, which prevents the necessary hybridization to the RNA template.

  • Owing to their mode of action, quadruplex-binding ligands might offer the advantages of rapid onset of action, and activity against the ∼15% of tumour cells that maintain their telomeres through a telomerase-independent mechanism.

Abstract

Maintenance of telomeres — specialized complexes that protect the ends of chromosomes — is undertaken by the enzyme complex telomerase, which is a key factor that is activated in more than 80% of cancer cells that have been examined so far, but is absent in most normal cells. So, targeting telomere-maintenance mechanisms could potentially halt tumour growth across a broad spectrum of tumour types, with little cytotoxic effect outside tumours. Here, we describe the current understanding of telomere biology, and the application of this knowledge to the development of anticancer drugs.

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Figure 1: A schematic view of the t-loop structure of human telomeres.
Figure 2: The folding of telomeric DNA: guanine quadruplexes.
Figure 3: Telomere elongation by telomerase and its inhibition.
Figure 4: Structures of various telomerase inhibitors.
Figure 5: G-quadruplexes and telomerase inhibition.
Figure 6: Structure-based design of G-quadruplex ligands.

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Acknowledgements

We are grateful to M. Read for providing Figure 6, G. Chessan, S. Haider and C. Schultze for stimulating discussions, and Cancer Research UK for support of these studies.

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  1. CRC Biomolecular Structure Unit, Chester Beatty Laboratories, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK

    Stephen Neidle & Gary Parkinson

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ABL

ATM

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hTERT

hTR

HUS1

MAD1

MAX

MYC

p16

p53

RAD1

RAD9

Rb

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RAP1

SP1

TIN2

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Glossary

TOPOISOMERASE

An enzyme that changes DNA supercoiling by inserting or removing superhelical twists.

APOPTOSIS

Programmed cell death.

CHAPERONE

A protein that facilitates the proper folding of other proteins but does not bind to their final folded form.

DOMINANT-NEGATIVE

A defective protein that retains interaction capabilities and so distorts or competes with normal proteins.

HELICASE

An enzyme that separates the two DNA strands in a double helix, which results in the formation of regions of single-stranded DNA.

INTERCALATION

The insertion of a molecule (which is typically flat and aromatic) between adjacent base pairs of DNA.

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Neidle, S., Parkinson, G. Telomere maintenance as a target for anticancer drug discovery. Nat Rev Drug Discov 1, 383–393 (2002). https://doi.org/10.1038/nrd793

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