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Telomere biology: integrating chromosomal end protection with DNA damage response

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Abstract

Telomeres play the key protective role at chromosomes. Many studies indicate that loss of telomere function causes activation of DNA damage response. Here, we review evidence supporting interdependence between telomere maintenance and DNA damage response and present a model in which these two pathways are combined into a single mechanism for protecting chromosomal integrity. Proteins directly involved in telomere maintenance and DNA damage response include Ku, DNA-PKcs, RAD51D, PARP-2, WRN and RAD50/MRE11/NBS1 complex. Since most of these proteins participate in the repair of DNA double-strand breaks (DSBs), this was perceived by many authors as a paradox, given that telomeres function to conceal natural DNA ends from mechanisms that detect and repair DSBs. However, we argue here that the key function of one particular DSB protein, Ku, is to prevent or control access of telomerase, the enzyme that synthesises telomeric sequences, to both internal DSBs and natural chromosomal ends. This view is supported by observations that Ku has a high affinity for DNA ends; it acts as a negative regulator of telomerase and that telomerase itself can target internal DSBs. Ku then directs other DSB repair/telomere maintenance proteins to either repair DSBs at internal chromosomal sites or prevent uncontrolled elongation of telomeres by telomerase. This model eliminates the above paradox and provides a testable scenario in which the role of DSB repair proteins is to protect chromosomal integrity by balancing repair activities and telomere maintenance. In our model, a close association between telomeres and different DNA damage response factors is not an unexpected event, but rather a logical result of chromosomal integrity maintenance activities.

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Acknowledgements

Work in the laboratory of P. S. is supported by grants from the Department of Health (RRX97) and the European Commission Euratom programme (contract FIGH-CT-2002-00217). S. A. W. is supported by a doctoral fellowship from the Saudi Arabia Ministry of Health. We would like to apologise to those authors whose works may be relevant for this review, but were not quoted due to space limitation.

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  1. Brunel Institute of Cancer Genetics and Pharmacogenomics, Division of Biosciences, School of Health Sciences and Social Care, Brunel University, Uxbridge, Middlesex, UB8 3PH, UK

    Predrag Slijepcevic & Suliman Al-Wahiby

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  1. Predrag Slijepcevic
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Correspondence to Predrag Slijepcevic.

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Communicated by D. Griffin

Review related to the 15th International Chromosome Conference (ICC XV), held in September 2004, Brunel University, London, UK

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Slijepcevic, P., Al-Wahiby, S. Telomere biology: integrating chromosomal end protection with DNA damage response. Chromosoma 114, 275–285 (2005). https://doi.org/10.1007/s00412-005-0338-4

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