DNA damage in telomeres and mitochondria during cellular senescence: is there a connection?
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.
Passos
João F
JF
Henry Wellcome Laboratory for Biogerontology Research, Institute for Ageing and Health, University of Newcastle, Newcastle upon Tyne NE4 6BE, UK.
Saretzki
Gabriele
G
von Zglinicki
Thomas
T
D016922:Cellular Senescence / Q000235:genetics*; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000737:chemistry; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000378:metabolism*
D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D019098:Telomerase