The aging syndrome arguably results from cumulative effects of chronic oxidative stress caused by reactive oxygen species (ROS), generated mostly in the mitochondria (mt). Both the nuclear and mitochondrial genomes are among the targets of ROS, in which the damage is repaired primarily via the DNA base excision repair pathway with AP-endonuclease (APE) playing a central role. The mt APE, involved in the repair of mtDNA damage, is generated by N-terminal cleavage of the major mammalian nuclear APE (APE1). APE1 is also a transcriptional regulator, both as a reductive activator of transcription factors (TF), such as p53 and hypoxia inducible factor (HIF), and as a TF in its own right, by binding to negative Ca 2+ response elements (nCaRE) and shear stress response elements (SSRE). This binding activity is enhanced by its acetylation. An age-dependent decline in the expression of many genes containing these cis elements, and decreased in the acetylated APE1 (AcAPE1) level suggest that activities of the TFs binding to these elements, including APE1, are affected by aging. In keeping with the broad objective of the Program Project to elucidate the role ofmt-generated oxidative stress in aging, the goal of Project 2 is to use livers and isolated hepatocytes from wild-type and transgenic young, middle aged and old mice. The wild type and transgenic animals express altered levels of nuclear and mtAPE. Shear stress-sensitive primary endothelial cells which undergo replicative senescence will also be used in a variety of molecular and cell biological approaches, to examine APE's bipartite functions in repairing nuclear and mtDNA damage, and in regulating age-modulated expression of SSRE-, and nCaRE-dependent genes. We will collaborate with Projects 1 and 3 to: (1) examine whether AcAPE1 and APE1 levels are affected by aging, leading to diminished cellular responses to oxidative stress; (2) test whether APE1 and mtAPE are limiting in repair ofROS-induced DNA damage, leading to aging-dependent accumulation of such damage, and to nat dysfunction; (3) examine aging-dependent modulation of SSRE-, nCaRE-dependent activation of genes in mice and isolated hepatocytes with altered APE or mtAPE levels, and the effect on the life span and cognitive functions of these animals; and (4) identify genes affected by altered APE levels in transgenic mice, by genomic and proteomic analysis. These studies should provide important new insights into the role of nuclear and mt DNA damage in sustaining oxidative stress, and of APE 1 in age-dependent modulation of signaling pathways.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
1P01AG021830-01A2
Application #
6814767
Study Section
Special Emphasis Panel (ZAG1-ZIJ-8 (M2))
Project Start
2004-07-01
Project End
2009-06-30
Budget Start
2004-07-01
Budget End
2005-07-31
Support Year
1
Fiscal Year
2004
Total Cost
$223,344
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Type
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
German, Peter; Saenz, David; Szaniszlo, Peter et al. (2017) 8-Oxoguanine DNA glycosylase1-driven DNA repair-A paradoxical role in lung aging. Mech Ageing Dev 161:51-65
Bacsi, Attila; Pan, Lang; Ba, Xueqing et al. (2016) Pathophysiology of bronchoconstriction: role of oxidatively damaged DNA repair. Curr Opin Allergy Clin Immunol 16:59-67
Al-Lahham, Rabab; Deford, James H; Papaconstantinou, John (2016) Mitochondrial-generated ROS down regulates insulin signaling via activation of the p38MAPK stress response pathway. Mol Cell Endocrinol 419:1-11
Papaconstantinou, John; Wang, Chen Z; Zhang, Min et al. (2015) Attenuation of p38? MAPK stress response signaling delays the in vivo aging of skeletal muscle myofibers and progenitor cells. Aging (Albany NY) 7:718-33
Hegde, Pavana M; Dutta, Arijit; Sengupta, Shiladitya et al. (2015) The C-terminal Domain (CTD) of Human DNA Glycosylase NEIL1 Is Required for Forming BERosome Repair Complex with DNA Replication Proteins at the Replicating Genome: DOMINANT NEGATIVE FUNCTION OF THE CTD. J Biol Chem 290:20919-33
Papaconstantinou, John; Hsieh, Ching-Chyuan (2015) IGF-1 mediated phosphorylation of specific IRS-1 serines in Ames dwarf fibroblasts is associated with longevity. Oncotarget 6:35315-23
Ba, Xueqing; Aguilera-Aguirre, Leopoldo; Sur, Sanjiv et al. (2015) 8-Oxoguanine DNA glycosylase-1-driven DNA base excision repair: role in asthma pathogenesis. Curr Opin Allergy Clin Immunol 15:89-97
Vlahopoulos, Spiros A; Cen, Osman; Hengen, Nina et al. (2015) Dynamic aberrant NF-?B spurs tumorigenesis: a new model encompassing the microenvironment. Cytokine Growth Factor Rev 26:389-403
Radak, Z; Ihasz, F; Koltai, E et al. (2014) The redox-associated adaptive response of brain to physical exercise. Free Radic Res 48:84-92
Luo, Jixian; Hosoki, Koa; Bacsi, Attila et al. (2014) 8-Oxoguanine DNA glycosylase-1-mediated DNA repair is associated with Rho GTPase activation and ?-smooth muscle actin polymerization. Free Radic Biol Med 73:430-8

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