Abstract

This is a competitive renewal to continue Dr. Jacobson's studies into alterations in NAD metabolism following exposure to chemical carcinogens. Specifically, the objective of this application is to understand mechanisms of ADP-ribosylation following exposure to an alkylating toxin.
Three aims have been proposed. The first is to systematically characterize noncovalent interactions of ADPR polymers with chromatin proteins, with the goal of elucidating factors that govern these interactions. Adiitionally, the chromatin proteins that interact noncovalently with ADPR polymers in intact cells will be identified.
The second aim i s to determine the structure of poly ADPR glycohydrolase, and assess its function in cellular recovery from DNA damage.
The final aim will characterize carcinogen-induced protein glycation by ADPR, and to examine the role of protein ADPR lyase and/or other enzymes in the removal of ADPR polymer remnants and/or products of glycation.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA043894-11
Application #
2091305
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1986-04-01
Project End
1998-06-30
Budget Start
1995-07-06
Budget End
1996-06-30
Support Year
11
Fiscal Year
1995
Total Cost
Indirect Cost

  Institution

Name
University of Kentucky
Department
Chemistry
Type
Schools of Pharmacy
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506

  Publications

Benavente, Claudia A; Schnell, Stephanie A; Jacobson, Elaine L (2012) Effects of niacin restriction on sirtuin and PARP responses to photodamage in human skin. PLoS One 7:e42276
Tome, Margaret E; Frye, Jennifer B; Coyle, Donna L et al. (2012) Lymphoma cells with increased anti-oxidant defenses acquire chemoresistance. Exp Ther Med 3:845-852
Bermudez, Yira; Benavente, Claudia A; Meyer, Ralph G et al. (2011) Nicotinic acid receptor abnormalities in human skin cancer: implications for a role in epidermal differentiation. PLoS One 6:e20487
Steffen, Jamin D; Coyle, Donna L; Damodaran, Komath et al. (2011) Discovery and structure-activity relationships of modified salicylanilides as cell permeable inhibitors of poly(ADP-ribose) glycohydrolase (PARG). J Med Chem 54:5403-13
Botta, Davide; Jacobson, Myron K (2010) Identification of a regulatory segment of poly(ADP-ribose) glycohydrolase. Biochemistry 49:7674-82
Williams, Joshua D; Jacobson, Myron K (2010) Photobiological implications of folate depletion and repletion in cultured human keratinocytes. J Photochem Photobiol B 99:49-61
Whatcott, Clifford J; Meyer-Ficca, Mirella L; Meyer, Ralph G et al. (2009) A specific isoform of poly(ADP-ribose) glycohydrolase is targeted to the mitochondrial matrix by a N-terminal mitochondrial targeting sequence. Exp Cell Res 315:3477-85
Benavente, Claudia A; Jacobson, Myron K; Jacobson, Elaine L (2009) NAD in skin: therapeutic approaches for niacin. Curr Pharm Des 15:29-38
Young, Genevieve S; Kirkland, James B (2008) The role of dietary niacin intake and the adenosine-5'-diphosphate-ribosyl cyclase enzyme CD38 in spatial learning ability: is cyclic adenosine diphosphate ribose the link between diet and behaviour? Nutr Res Rev 21:42-55
Benavente, Claudia A; Jacobson, Elaine L (2008) Niacin restriction upregulates NADPH oxidase and reactive oxygen species (ROS) in human keratinocytes. Free Radic Biol Med 44:527-37

Showing the most recent 10 out of 81 publications