Abstract

DNA damage can elicit a variety of cellular responses including 1) inhibition of DNA replication, transcription and progression through the cell cycle, 2) cell death, and 3) mutagenesis. These biological consequences of DNA damage can perturb normal cellular function and impact health span. Organisms have evolved with genome safeguarding mechanisms, such as DNA repair pathways, to minimize the deleterious effects of DNA damage. Regardless, DNA damage and mutagenesis increase with age in a variety of tissues, thereby endangering health span. The decreased genetic integrity associated with older age corresponds to decreased base excision repair activity, and decreased DNA polymerase -beta activity/abundance in some tissues. The purpose of the proposed studies is to determine the extent to which DNA polymerase-beta dependent base excision repair (BER) contributes to genomic integrity, health span and lifespan. Lacking a proofreading activity, DNA polymerase-beta has a relatively low fidelity. Brain tissue in transgenic mice carrying a mutational reporter transgene do not display an increased mutant frequency with older ages, but mice do exhibit decreased BER and a reduced DNA polymerase-beta activity in brain of older animals. In contrast, male germ cells obtained from young adult DNA polymerase-beta heterozygous knockout mice display an increased spontaneous mutant frequency. These and other data suggest that changes in DNA polymerase-beta activity could mediate different effects among mammalian tissues. The overall hypothesis to be tested is that modulation of DNA polymerase beta abundance/activity will have differential effects among tissues relative to age. Mouse models, and cell lines derived from the mouse models, with normal, enhanced or reduced DNA polymerase-beta expression/activity will be used to examine the potentially protective and deleterious effects of altered DNA polymerase-beta activity. Genetic integrity, apoptosis, and pathology will be examined using a variety of molecular, biochemical and cell biological approaches.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG024364-02
Application #
6951036
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5 (M3))
Program Officer
Mccormick, Anna M
Project Start
2004-09-30
Project End
2009-07-31
Budget Start
2005-08-15
Budget End
2006-07-31
Support Year
2
Fiscal Year
2005
Total Cost
$341,496
Indirect Cost

  Institution

Name
University of Texas Health Science Center San Antonio
Department
Anatomy/Cell Biology
Type
Other Domestic Higher Education
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229

  Publications

Sanchez, Jamila R; Reddick, Traci L; Perez, Marissa et al. (2015) Increased human AP endonuclease 1 level confers protection against the paternal age effect in mice. Mutat Res 779:124-33
Xu, Guogang; McMahan, C Alex; Hildreth, Kim et al. (2012) Ionizing radiation-induced mutant frequencies increase transiently in male germ cells of older mice. Mutat Res 744:135-9
Vogel, Kristine S; Perez, Marissa; Momand, Jamila R et al. (2011) Age-related instability in spermatogenic cell nuclear and mitochondrial DNA obtained from Apex1 heterozygous mice. Mol Reprod Dev 78:906-19
Tang, Jiang-bo; Goellner, Eva M; Wang, Xiao-hong et al. (2010) Bioenergetic metabolites regulate base excision repair-dependent cell death in response to DNA damage. Mol Cancer Res 8:67-79
Asagoshi, Kenjiro; Liu, Yuan; Masaoka, Aya et al. (2010) DNA polymerase beta-dependent long patch base excision repair in living cells. DNA Repair (Amst) 9:109-19
Jelezcova, Elena; Trivedi, Ram N; Wang, Xiao-Hong et al. (2010) Parp1 activation in mouse embryonic fibroblasts promotes Pol beta-dependent cellular hypersensitivity to alkylation damage. Mutat Res 686:57-67
Allen, Diwi; Herbert, Damon C; McMahan, C Alex et al. (2008) Mutagenesis is elevated in male germ cells obtained from DNA polymerase-beta heterozygous mice. Biol Reprod 79:824-31
Kronenberg, Golo; Harms, Christoph; Sobol, Robert W et al. (2008) Folate deficiency induces neurodegeneration and brain dysfunction in mice lacking uracil DNA glycosylase. J Neurosci 28:7219-30
Trivedi, Ram N; Wang, Xiao-hong; Jelezcova, Elena et al. (2008) Human methyl purine DNA glycosylase and DNA polymerase beta expression collectively predict sensitivity to temozolomide. Mol Pharmacol 74:505-16
Xu, Guogang; Intano, Gabriel W; McCarrey, John R et al. (2008) Recovery of a low mutant frequency after ionizing radiation-induced mutagenesis during spermatogenesis. Mutat Res 654:150-7

Showing the most recent 10 out of 14 publications