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Nucleic Acids Res. 2007;35(22):7505-13. Epub 2007 Nov 5.

DNA damage in telomeres and mitochondria during cellular senescence: is there a connection?

Author information

  • 1Henry Wellcome Laboratory for Biogerontology Research, Institute for Ageing and Health, University of Newcastle, Newcastle upon Tyne NE4 6BE, UK.

Abstract

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.

PMID:
17986462
[PubMed - indexed for MEDLINE]
PMCID:
PMC2190715
Free PMC Article

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