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

Lookup NU author(s): Dr Joao Passos, Dr Gabriele Saretzki, Professor Thomas von Zglinicki

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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. © 2007 The Author(s).


Publication metadata

Author(s): Passos J, Saretzki G, von Zglinicki T

Publication type: Article

Publication status: Published

Journal: Nucleic Acids Research

Year: 2007

Volume: 35

Issue: 22

Pages: 7505-7513

ISSN (print): 0305-1048

ISSN (electronic): 1362-4954

Publisher: Oxford University Press

URL: http://dx.doi.org/10.1093/nar/gkm893

DOI: 10.1093/nar/gkm893

PubMed id: 17986462


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