Pathology & Laboratory Medicine

Isabel Mellon,  Ph.D.

Associate Professor

E-mail: mellon@uky.edu
Telephone:   (859) 257-6253
Fax:   (859) 323-2094
Campus Address:  Graduate Center for Toxicology, 220 Multidisciplinary Research Lab, 0216

My laboratory studies DNA repair mechanisms and we are interested in how alterations in DNA repair impact disease processes. Nucleotide excision repair (NER) is a major pathway for the removal of cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts produced by UV light. It also removes a wide variety of bulky adducts formed by chemical agents or carcinogens. It is a complex multi-step process that is comprised of two subpathways in E. coli, yeast and mammals. One subpathway is termed transcription-coupled repair (TCR) which selectively removes lesions from the transcribed strands of expressed genes. This subpathway of DNA repair I co-discovered with Philip Hanawalt and colleagues. The other subpathway is termed global genome repair (GGR) which removes lesions from the remainder of the genome. There are 3 areas related to nucleotide excision repair that we are currently investigating.

(1) Inherited defects in NER genes predispose humans to cancer, predominantly skin cancer. This is clearly illustrated by the disease xeroderma pigmentosum (XP). We are currently investigating whether polymorphisms and/or acquired somatic mutations in NER genes can also be involved in the etiology of certain types of cancer. We are focused on skin cancer and lung cancer because the etiology of both forms of cancer is clearly linked to agents that introduce bulky adducts that are substrates for NER. We are characterizing cell lines derived from different tumor types for alterations in NER. In addition, we are searching for novel polymorphic alleles and are carrying out structure/function studies to investigate the functional significance of polymorphisms in NER genes.

(2) Certain chemotherapeutic agents introduce lesions that are removed by nucleotide excision repair. The efficacy of some types of chemotherapeutic agents in killing tumor cells may be related to differences in the efficiency of nucleotide excision repair. We are currently comparing nucleotide excision repair levels in cell lines derived from different types of tumors that respond well to certain chemotherapeutic agents vs those that respond poorly.

(3) TCR is clearly a subpathway of NER and is generally observed as more rapid removal of lesions from the transcribed strands of expressed genes compared with the nontranscribed strands. It operates on a wide spectrum of lesions that generally block RNA polymerase elongation. While the precise mechanism of TCR remains to be elucidated, an early event likely involves blockage of the RNA polymerase complex at lesions present in the transcribed strands of expressed genes. We are currently investigating mechanisms of TCR in bacterial and mammalian systems.