Reactive oxygen species (ROS) are implicated in the etiology &aging by causing a decline in tissue functions due to altered cellular signaling cascades that maintain cellular homeostasis, and by inducing damage to cellular components, including DNA. 8-Oxoguanine (8-oxoG), and ring-opened purine (FapyG), the two abundant mutagenic and toxic base lesions induced by ROS, are repaired primarily by 8-oxoG-DNA glycosylase (OGGI), with spliced variants, OGGI-1 a and OGG1-2a, targeted to nucleus and mitochondria (mr), respectively. In ogg 14-mouse cells, these lesions accumulate in both nuclear and mtDNA, associated with enhanced mutagenesis, and spontaneous tung carcinoma. At the same time, lack of efficient nuclear import of OGG 1-1 a and accumulation of damage in the genome of senescence-accelerated mice support the etiologic involvement of 8-oxoG/FapyG in aging processes. Paradoxically, age-dependent accumulation of 8-oxoG/FapyG in nuclear and mtDNA occurs without a decline in total OGG1 activity. This discrepancy could be explained by our results showing poor mt import of OGG 1-2a in senescent cells so that a significant fraction of the enzyme remains bound to the outer mt membrane. Furthermore, nuclear accumulation of OGG1-1 a induced by ROS is delayed in the aged cells. The central hypothesis of this project is that toxic and mutagenic oxidative DNA lesions accumulate due to a decreased ability of aged cells to maintain normal levels of OGG 1 in the nucleus and mt thereby causing a decline in tissue functions. Using a variety of cellular, molecular and transgenic approaches, and in collaboration with P1 and P2, we will test our hypothesis with the following aims: 1) to explore the mechanism of age-dependent deficiency in repair of oxidative lesions after oxidative challenge; 2) to validate the preliminary observation that the delay in OGG1 nuclear accumulation is linked to its covalent modification (e.g., acetylation) identified in OGG1-la; and 3) to confirm that accumulation of 8-oxoG/FapyG in the mtDNA of aged cells is indeed due to reduced repair caused by inefficient targeting of OGG1-2a to the mt matrix, which is affected by ROS. These studies will shed significant light on the accumulation of the major mutagenic and toxic lesions in the aging process. The long-term objective is to develop intervention strategies to ameliorate an age-associated decrease in repair of mutagenic DNA lesions in the nucleus and rot, and thus to delay the decline in mitochondria and cellular functions.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
1P01AG021830-01A2
Application #
6814768
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
$224,166
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Type
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
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