Human telomeres shorten during each cell division, predominantly because of incomplete DNA replication. This eventually results in short uncapped telomeres that elicit a DNA-damage response, leading to cellular senescence. However, evasion of senescence results in continued cell division and telomere erosion ultimately results in genome instability. In the long term, this genome instability is not sustainable, and cancer cells activate a TMM (telomere maintenance mechanism), either expression of telomerase or activation of the ALT (alternative lengthening of telomeres) pathway. Activation of the ALT mechanism results in deregulation of recombination-based activities at telomeres. Thus ALT+ cells show elevated T-SCE (telomere sister-chromatid exchange), misprocessing of t-loops that cap chromosomes and recombination-based processes between telomeres or between telomeres and ECTRs (extrachromosomal telomeric repeats). Some or all of these processes underlie the chaotic telomere length maintenance that allows cells in ALT+ tumours unlimited replicative capacity. ALT activation is also associated with destabilization of a minisatellite, MS32. The connection between the minisatellite instability and the deregulation of recombination-based activity at telomeres is not understood, but analysis of the minisatellite can be used as a marker for ALT. It is known that telomere length maintenance in ALT+ cells is dependent on the MRN [MRE11 (meiotic recombination 11)–Rad50–NBS1 (Nijmegen breakage syndrome 1)] complex, but knowledge of the role of other genes, including the Werner's (WRN) and Bloom's (BLM) syndrome DNA helicase genes, is still limited.
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June 2009
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Conference Article|
May 20 2009
The role of recombination in telomere length maintenance
Nicola J. Royle;
Nicola J. Royle
1
1Department of Genetics, University of Leicester, University Road, Leicester LE1 7RH, U.K.
1To whom correspondence should be addressed (email njr@le.ac.uk).
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Aarón Méndez-Bermúdez;
Aarón Méndez-Bermúdez
1Department of Genetics, University of Leicester, University Road, Leicester LE1 7RH, U.K.
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Athanasia Gravani;
Athanasia Gravani
1Department of Genetics, University of Leicester, University Road, Leicester LE1 7RH, U.K.
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Clara Novo;
Clara Novo
1Department of Genetics, University of Leicester, University Road, Leicester LE1 7RH, U.K.
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Jenny Foxon;
Jenny Foxon
1Department of Genetics, University of Leicester, University Road, Leicester LE1 7RH, U.K.
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Jonathan Williams;
Jonathan Williams
1Department of Genetics, University of Leicester, University Road, Leicester LE1 7RH, U.K.
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Victoria Cotton;
Victoria Cotton
1Department of Genetics, University of Leicester, University Road, Leicester LE1 7RH, U.K.
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Alberto Hidalgo
Alberto Hidalgo
1Department of Genetics, University of Leicester, University Road, Leicester LE1 7RH, U.K.
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Publisher: Portland Press Ltd
Received:
December 15 2008
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2009 Biochemical Society
2009
Biochem Soc Trans (2009) 37 (3): 589–595.
Article history
Received:
December 15 2008
Citation
Nicola J. Royle, Aarón Méndez-Bermúdez, Athanasia Gravani, Clara Novo, Jenny Foxon, Jonathan Williams, Victoria Cotton, Alberto Hidalgo; The role of recombination in telomere length maintenance. Biochem Soc Trans 1 June 2009; 37 (3): 589–595. doi: https://doi.org/10.1042/BST0370589
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