Nucleic Acids Research Advance Access originally published online on November 5, 2007
Nucleic Acids Research 2007 35(22):7505-7513; doi:10.1093/nar/gkm893
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Nucleic Acids Research, 2007, Vol. 35, No. 22 7505-7513
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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DNA damage in telomeres and mitochondria during cellular senescence: is there a connection?
1Henry Wellcome Laboratory for Biogerontology Research, Institute for Ageing and Health, University of Newcastle, Newcastle upon Tyne NE4 6BE, UK, 2Center for Integrated Systems Biology of Ageing and Nutrition (CISBAN), University of Newcastle, Newcastle upon Tyne NE4 6BE, UK and 3Crucible Laboratory, Life Knowledge Park, Institute for Ageing and Health, Newcastle University, NE1 3BZ, UK
*To whom correspondence should be addressed: Tel: +44 191 256 3310; Fax: +44 191 256 3445; Email: t.vonzglinicki{at}ncl.ac.uk
Received July 17, 2007. Revised October 2, 2007. Accepted October 2, 2007.
Cellular senescence is the ultimate and irreversible loss of replicative capacity occurring in primary somatic cell culture. It is triggered as a stereotypic response to unrepaired nuclear DNA damage or to uncapped telomeres. In addition to a direct role of nuclear DNA double-strand breaks as inducer of a DNA damage response, two more subtle types of DNA damage induced by physiological levels of reactive oxygen species (ROS) can have a significant impact on cellular senescence: Firstly, it has been established that telomere shortening, which is the major contributor to telomere uncapping, is stress dependent and largely caused by a telomere-specific DNA single-strand break repair inefficiency. Secondly, mitochondrial DNA (mtDNA) damage is closely interrelated with mitochondrial ROS production, and this might also play a causal role for cellular senescence. Improvement of mitochondrial function results in less telomeric damage and slower telomere shortening, while telomere-dependent growth arrest is associated with increased mitochondrial dysfunction. Moreover, telomerase, the enzyme complex that is known to re-elongate shortened telomeres, also appears to have functions independent of telomeres that protect against oxidative stress. Together, these data suggest a self-amplifying cycle between mitochondrial and telomeric DNA damage during cellular senescence.
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