Paul

Miller

,

PhD

My laboratory uses nucleic acid chemistry and biochemistry to study biological problems. We are currently pursing research in three different areas. The first area involves studying the mechanism(s) of DNA interstrand cross-link repair in mammalian cells. DNA interstrand cross-links are created by cancer chemotherapeutic agents such bischloroethylnitrosourea (BCNU) and by electrophiles such as malondialdehyde that produced in the intracellular environment by lipid peroxidation. We have developed methods to synthesize short DNA duplexes that contain interstrand cross-links of defined structure and orientation. These cross-linked duplexes are incorporated into longer linear DNA duplexes to study cross-link processing in cell extracts, and into reporter plasmids to study cross-link repair in mammalian cells. The second research area focuses on developing platinum-derivatized triplex-forming oligonucleotides that are targeted to polypurine tracts that occur in the promoter and coding regions of the human androgen receptor gene, whose expression is necessary for survival of prostate cancer cells. These oligonucleotides are designed to bind irreversibly to their target DNA and prevent transcription of the DNA. The long term goal of this research is to develop agents that can inhibit replication of prostate tumor cells. The third area of research focuses on studying the effects of oxidative stress on genome integrity and DNA repair capacity in mammalian cells. Toward this end, we are currently developing nucleic acid based biosensors that are able to detect oxidized nucleosides in DNA derived from mammalian cells that have been subjected to oxidative stress.