Age-dependent modulation of DNA repair enzymes by covalent modification and subcellular distribution.
Chronic oxidative stress is generally believed to be a major etiologic factor in the aging process. In addition to modulation of signaling processes and oxidation of cellular proteins and lipids, reactive oxygen species (ROS) induce multiple damages in both nuclear and mitochondrial genomes, most of which are repaired via the DNA base excision repair pathway. 8-Oxoguanine (8-oxoG), a major ROS product in the genome, is excised by 8-oxoG-DNA glycosylase (OGG1) and the resulting abasic (AP) site is cleaved by AP-endonuclease (APE1) in the initial steps of repair. Here, we provide data showing that differences between young and aged cells' efficiency in import of OGG1 and APE1 may be responsible for age-associated increase in DNA damage in both nuclear and mitochondrial compartments. It is also evident that age-dependent changes in covalent modifications of APE1 by acetylation regulate its action as a transcriptional repressor of many Ca(2+)-responsive genes by binding to nCaRE, in addition to its endonuclease activity. Thus, ROS-induced altered signaling is responsible for age-dependent changes in post-translational modifications and import of DNA repair enzymes into nuclei and mitochondria (mt), which in turn affect repair of their genomes.
Szczesny
Bartosz
B
Sealy Center for Molecular Science, University of Texas Medical Branch, 6.136 Medical Research Building, Route 1079, Galveston, TX 77555, USA.
Bhakat
Kishor K
KK
Mitra
Sankar
S
Boldogh
Istvan
I
D000375:Aging / Q000378:metabolism*; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism*; D045647:DNA Glycosylases / Q000378:metabolism*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D017382:Reactive Oxygen Species; D004247:DNA; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse; C479058:oxoguanine glycosylase 1, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase