Research Interests

Cells of the human body are continuously exposed to agents which damage their DNA and lead to genetic alterations.  As part of the normal homeostatic mechanisms of the cell, there are a group of proteins which are collectively referred to as DNA repair enzymes.  These enzymes survey the DNA, recognize abnormalities, remove them and return the DNA to its normal sequence and configuration.  Any decrease in the capacity or efficiency of these repair mechanisms can lead to an increase in genetic instability which is a hallmark characteristic of diseases such as cancer.  The major areas of interest in this laboratory involve the role that DNA repair of environmentally induced damage plays in diseases of the central nervous system. 

Initially, DNA repair studies assessed repair across the entire genome.  However, as our knowledge of gene structure improved concomitantly with the introduction of new technologies, it has become apparent that DNA repair of many types of lesions is not homogenous across the entire genome.  Therefore, this laboratory investigates DNA repair using techniques to quantitatively measure the formation and removal of DNA lesions across the entire genome, within specific nuclear and mitochondrial sequences, and by using ligation_mediated PCR at the level of individual nucleotides. 

EDUCATION

ACADEMIC APPOINTMENTS                                   

ACADEMIC AND PROFESSIONAL HONORS

Outstanding Basic Sciences Teacher; 5/00
Independent Scientist Award; 9/01/97-8/31/02
Participant in NCI Short Term Scientist Exchange Program; 1/18/93 - 3/13/93
American Cancer Society, Junior Faculty Research Award, 1991-1993
NIH Postdoctoral Fellowship, 1988-1990
JDF Postdoctoral Fellowship, declined in lieu of NIH Postdoctoral Fellowship
NDEA TITLE IV Fellowship, 1969-1972
 

CONSULTANTSHIPS

EXTRAMURAL FUNDING

a) NIH; ES 05865: R01; Repair of DNA Damage Induced by Environmental Agents; 7/01/00- 6/30/05; Susan LeDoux P.I., 50%; $630,464 total support.

b) NIH; ES 00313: K02; Repair of DNA Damage Induced by Environmental Agents; 9/01/97- 8/31/02;$341,388, total support.

c) NIH; ES 03456: Environmental Beta Cell Toxins; Mechanisms of Action; 7/1/01- 6/30/06; G. L. Wilson , P.I.; 10%; $810,872, total support.

d) NIH; AG19602; Oxidative Damage and Repair in Neuronal mtDNA; 9/30/00-8/31/05: G. L. Wilson, PI, 10%; $883,072 total support.

e) NIH; PO1 HL 66299; Mitochondrial DNA Integrity in Lung Endothelial Cells;09/24/01-07/31/06: M.N. Gillespie, PI; S.P. LeDoux, Co PI; $1,101,705 total support.
 

PUBLICATIONS

Druzhyna, N.M., Hollensworth S.B., Kelley M.R.,Wilson G.L. and LeDoux, S.P. Targeting Human 8-Oxoguanine Glycosylase to Mitochondria of Oligodendrocytes Protects Against Menadione-Induced Oxidative Stress. Glia (Submitted 2002). 
 
Shokolenko, I.N., Alexeyev, M.F., Robertson, F.M., LeDoux, S.P., and Wilson, G.L. The expression of exonuclease III from E.coli in mitochondria of breast cancer cells diminishes mitochondrial DNA repair capacity and cell survival after oxidative stress. Cancer Res. (Submitted 2002). 
 
Grishko, V., Killilea, D.W., Ault-Ziel, K., LeDoux, S.P., Wilson, G.L., and Gillespie, M.N. Formation and repair of oxidant-mediated DNA modifications in hypoxic pulmonary artery smooth muscle cells. Amer. J. Physiol.: Lung Cell Molec. Physiol. (Submitted 2002). 
 
Rachek, L.I., Grishko, V.I., Musiyenko, S.I., Kelley, M.R., LeDoux, S.P. and Wilson, G. L. Conditional targeting of the DNA repair enzyme hOGG1 into mitochondria. J. Biol. Chem. 277:44932-7 (2002). 
 
Dobson, A.W., Grishko, V., LeDoux, S.P., Kelley, M.R., Wilson, G.L., and Gillespie, M.N. Enhanced mitochondrial DNA repair capacity protects pulmonary artery endothelial cells of oxidant-mediated death. Amer. J. Physiol.: Lung Cell Molec. Physiol. 283:(1):L205-10. (2002) 

Dobson, A. W., Kelley M. R.,Wilson, G.L., and LeDoux, S.P. Targeting DNA Repair Proteins to Mitochondria. In: Mitochondrial DNA; Methods and Protocols. (Ed. W.C. Copeland) Humans Press, pp.351-362 (2002).

LeDoux, S.P.  And Wilson, G.L. Base Excision Repair of Mitochondrial DNA Damage in Mammalian Cells. Prog. Nucleic Acid Res. Mol. Biol. 68:273-84 (2001).
 
Shokolenko, I., Oberyszyn T.M., D’Ambrosio, S.M., Saavedra J.E., Keefer, L.K., LeDoux, S.P., Wilson, G.L. Protection of human keratinocyte mtDNA by low-level nitric oxide. Nitric Oxide 5:555-560 (2001)

Grishko, V., Solomon, M., Wilson, G. L., LeDoux, S.P., and Gillespie, M.N. Oxygen radical-induced mitochondrial Dna damage and Repair in Pulmonary Bascular Endothelial Cell Phenotypes. Am. J. Physiol. Lung Cell. Mol. Physiol. 280:L1300-8 (2001).

Grishko V., Solomon, M., Breit, J.F., Killilea D.W., LeDoux, S.P. Wilson, G.L. and Gillespie, M.N. Hypoxia promotes oxidative base modifications in the pulmonary artery endothelial cell VEGF gene. FASEB J. 15:1267-1269 (2001).
 
LeDoux, S.P., Driggers, W.J., Dobson, A.W., and Wilson, G.L,. Measurement of Oxidative Lesions in Specific Mitochondrial and Nuclear DNA Sequences. In: Models and Methods in Cell Signaling and Gene Expression: Application to Oxidative Stress Research. (Ed T.M. Bray and N. W. Schone) OICA International. pp. 56-70 (2000).
 
Dobson, A.W., Xu, Y., Kelley, M.R., LeDoux, S.P., and Wilson, G. L. Enhanced mtDNA Repair and Cellular Survival Following Oxidative Stress by Targeting the hOGG Repair Enzyme to Mitochondria. J. Biol. Chem.275: 37518-37523 (2000).
 
Hollensworth, B.S., Shen,C., Sim,J.E., Spitz,D.R., Wilson,G.L., and LeDoux,S.P.  Glial Cell Type-Specific Responses to Menadione-Induced Oxidative Stress. Free Radical Biology and Medicine 28:1161-1174 (2000).
 
Rodriquez, H., Akman, S.A., Holmquist, G.P., Wilson, G.L., Driggers, W.J., and LeDoux, S.P. Mapping Oxidative DNA Damage Using LMPCR Technology. Methods 22:148-156 (2000).
 
Druzhyna. N., Smulson, M. E. LeDoux, S. P., and Wilson, G.L. Poly (ADP-Ribose) Polymerase Facilitates the Repair of N-Methylpurines in Mitochondrial DNA. Diabetes 49: 1849-1855 (2000).
 
Grishko, V. I., Druzhyna, N., LeDoux, S. P., and Wilson, G. L. Nitric Oxide-induced Damage to mtDNA and its Subsequent Repair, Nucleic Acids Res. 27:4510-4515 (1999). 
 
Pappolla, M.A., Chyan, Y-J., Poeggeler, B., Bozner, P., Ghiso, J., LeDoux, S.P., and Wilson, G.L. Alzheimer β protein mediated oxidative damage of mitochondrial DNA: Prevention by melatonin. J. Pineal Res. 27:226-229 (1999). 
 
LeDoux, S.P., Driggers, W.J., Hollensworth, B.S., and Wilson, G.L. Repair of Alkylation and Oxidative Damage in Mitochondrial DNA. Mutation Research 434:149-159 (1999).

Druzhyna, N., Nair, R.G., LeDoux, S.P., and Wilson, G.L. Defective Repair of Oxidative Damage in Mitochondrial DNA in Down’s Syndrome. Mutation Research 409:81-89 (1998).
 
LeDoux, S.P., Shen, C., Grishko, V.I., Fields, P.A., Gard, A.L., and Wilson, G.L. Glial Cell-specific Differences in Response to Alkylation Damage. Glia 24:304-312 (1998). 
 
Driggers, W.J., Holmquist, G.P., LeDoux, S.P., and Wilson, G.L. Mapping Frequencies of Endogenous Oxidative Damage and the Kinetic Response to Oxidative Stress in a Region of Rat mtDNA. Nucleic Acid Res. 25:4362-4369 (1997). 
 
Grishko, V.I., Driggers, W.J., LeDoux, S.P., and Wilson, G.L. Repair of Oxidative Damage in Nuclear DNA Sequences with Different Transcriptional Activities. Mutation Research 384:73-80 (1997). 
 
Wilson, G.L., Patton, N.J., and LeDoux, S.P. Mitochondrial DNA in Beta-cells is a Sensitive Target for Damage by Nitric Oxide. Diabetes 46:1291-1295 (1997).

Bozner, P., Grishko, V.I., LeDoux, S.P., Wilson, G.L., Chyan, Y-C., and Pappolla, M.A. The Amyloid β Protein Induces Oxidative Damage to Mitochondrial DNA. J. Neuropathology and Experimental Neurology 56:136-1362 (1997).

LeDoux, S.P., Williams, B.A., Hollensworth, B.S., Shen, C., Thomale, J., Rajewsky, M.F., Brent,T.P., and Wilson, G.L. Glial Cell-specific Differences in Repair of O6-methylguanine. Cancer Research 56:5615-5619 (1996).
 
Ray, L.S., Chatterjee, S., Berger, N.A., LeDoux, S.P., and Wilson, G.L. Catalytic Activity of Poly(ADP-ribose) Polymerase in Necessary for Repair of N-methylpurines in Nontranscribed, Nuclear Sequences Mutation Research 363:105-114 (1996). 
 
Driggers, W.J., Grishko,V.I., LeDoux, S.P., and Wilson, G.L. Defective Repair of Oxidative Damage in the Mitochondrial DNA of XP-A Cells. Cancer Research 56:1262-1266 (1996). 
 
Shen, C., Wertelecki, W. Driggers, W.J., LeDoux, S.P. and Wilson, G.L. Repair of Mitochondrial DNA Damage Induced by Bleomycin in Human Cells. Mutation Research 337:19-23 (1995). 
 
Driggers, W.J., LeDoux, S.P. and Wilson, G.L. Repair of Oxidative Damage within the Mitochondrial DNA of RINr 38 Cells. J. Biol. Chem. 268:22042-22045 (1993). 
 
Nelson, J.W., LeDoux, S.P. and Wilson, G.L. Repair of O6-methylguanine in Rat Pancreatic Beta Cells Following Exposure to N-methyl-N-nitrosourea. Diabetes 42: 1187-94 (1993). 
 
LeDoux, S.P., Patton, N.J., Avery, L.J. and Wilson, G.L. Repair of N-methylpurines in the Mitochondrial DNA of Xeroderma Pigmentosum Complementation Group D Cells. Carcinogenesis 14:913-917 (1993).
  
Wilson, G.L. and LeDoux, S.P. Interactions of Chemicals with Pancreatic B Cells: In: Frontiers In Diabetes Research: Lessons From Animal Diabetes, IV (E. Shafrir, Ed.) Smith-Gordon and Company Limited, London pp.17-26 (1993). 
 
LeDoux, S.P., Wilson, G.L. and Bohr, V.A. Mitochondrial DNA Repair and Cell Injury: In: Mitochondrial Dysfunction (D.P. Jones and L.H. Lash, Eds.) Academic Press, San Diego pp.461-476 (1993). 
 
LeDoux, S.P., Wilson, G.L. Beecham, E.J., Stevnsner, T., Wassermann, K. and Bohr, V.A. Repair of Mitochondrial DNA after Various Types of DNA Damage in Chinese Hamster Ovary Cells. Carcinogenesis 13: 1967-1973 (1992).  
 
LeDoux, S.P., Thangada, M., Bohr, V.A. and Wilson, G.L.: Heterogeneous Repair of Methylnitrosourea-induced Alkali-labile Sites in Different DNA Sequences. Cancer Research 51:775-779 (1991). 
 
Pettepher, C.C., LeDoux, S.P., Bohr, V.A. and Wilson, G.L.: Repair of Alkali-labile Sites within the Mitochondrial DNA of RINr 38 Cells after Exposure to the Nitrosourea Streptozotocin. J. Biol. Chem. 266:3113-3117, (1991). 
 
LeDoux, S.P., Patton, N.J., Nelson, J. W., Bohr, V.A. and Wilson, G.L.: Preferential DNA Repair of Alkali-labile Sites within the Active Insulin Gene. J. Biol. Chem. 265:14875-14880 (1990).

Wilson, G.L. and  LeDoux, S.P.: The Role of Chemicals in the Etiology of Diabetes Mellitus. Toxicol.Path. 17/2 357-363 (1989).
 
LeDoux, S.P., Hall, C.R., Forbes, P.M., Patton, N.J., and Wilson, G.L.: Mechanisms of Nicotinamide and Thymidine Protection from Alloxan and Streptozotocin Toxicity. Diabetes 37:1015-19 (1988).

Wilson, G.L., Hartig, P.C., Patton, N.J., and LeDoux, S.P.: Mechanisms of Nitrosourea-Induced Beta Cell Damage: Activation of Poly (ADP-ribose) Synthetase and Cellular Distribution. Diabetes 37: 213-216 (1988).

LeDoux, S.P., Woodley, S.E., Patton, N.J. and Wilson G.L.: Mechanisms of Nitrosourea-Induced Beta Cell Damage: Alterations in DNA. Diabetes 35:866-72 (1986). 
 
Mossman, B.T., Ireland, C.M., Filpak, M., LeDoux, S.P. and Wilson, G.L.: Comparative Interactions of Streptozotocin and Chlorozotocin with DNA of an Insulin-Secreting Cell Line (RINr). Diabetologia 29:186-191 (1986). 
 
LeDoux, S.P. and Wilson G.L.: Effects of streptozotocin on a clonal isolate of rat insulinoma cells. Biochim. Biophys Acta 804:387-92 (1984).