Mark R. Kelley, Ph.D.
Jonathan and Jennifer Simmons Professor: Department of Pediatrics
Associate Director: Wells Center for Pediatric Research
Associate Director for Basic Science: IU
Cancer Center
Clinical Section: Pediatric Hematology/Oncology
Basic Science Joint Appointments: Biochemisty and Molecular Biology, Pharmacology and Toxicology
Assistant Professor: Loyola University Medical School, Chicago, IL
Postdoctoral Fellowship: The Rockefeller University, New York, NY
Ph.D.: Louisiana State University, Baton Rouge, LA, 1984
Current Research Interests:
Molecular biology and biochemistry of eukaryotic DNA base excision repair (BER). Use of DNA repair genes for therapy in chemotherapeutic paradigms including the protection of normal cells from oxidative and alkylated DNA base damage and the killing of tumor cells. BER genes in cancer and neural cells.
Research:
The inherent chemical instability of DNA, the production of reactive oxygen species during normal cellular metabolism, and the continuous exposure to environmental mutagens and extraneous agents, such as during cancer chemotherapy, all represent a potential threat to the integrity of the DNA of cells. Our laboratory is mainly involved in understanding the differential expression and regulation of DNA repair genes involved in repairing base damage, along with using these DNA repair genes in gene therapy and translational applications.
Ongoing projects include:
1) Regulation, of AP endonuclease (Ape1/ref-1) in normal and cancer cells. The multifunctional mammalian APE is responsible for the repair of AP (abasic) sites in DNA. In addition, this enzyme has been shown to function as a redox factor facilitating the DNA-binding capability of numerous transcription factors (Fos, Jun, HIF-1(alpha), PAX, NFkB as well as p53. We are determining the relationship of the Ape1/ref-1 DNA repair enzyme to apoptosis, differentiation and redox control utilizing a variety of cells, tissues, and cell lines
Another avenue of study with APE/ref-1 involves its use as a cancer marker and understanding its role in tumor cells. We have shown that the Ape1/ref-1 protein is significantly and dramatically elevated in ovarian, prostate, cervical and germ cell tumors. We are currently trying to understand Ape1/ref-1's role in these cancers and others, and determining how to modulate its activity for therapeutic applications (small molecule inhibitors, siRNA, dominant-negative mutants).
2) One of the goals of various chemotherapy protocols concerns the protection of normal cells (e.g. bone marrow) from chemotherapeutic agents during the treatment of various cancers. We are exploring the use of members of the DNA base excision repair (BER) pathway in protecting cells from the cytotoxic effects of chemotherapeutic alkylating agents and ionizing radiation. We are currently focusing on the combined DNA glycosylase/lyases (Ogg, NTH1), along with other members of the BER pathways, such as MTH1, MYH, Ape1/ref-1 and various combinations. Those that show promise will be used in gene therapy protocols and transgenic animals to further pursue the usefulness of these genes in translational settings.
3) Oxidative DNA damage has been implicated in aging, neurological defects, and cancer. Additionally, a number of cancer chemotherapeutic agents produce oxidative DNA damage. We are studying endogenous and overexpressed oxidative DNA BER genes (Ogg1, NTH, MTH, and MYH) in order to determine which ones may be involved in mitotic and postmitotic oxidative DNA repair.
