Jim Liu, PhD
Professor College of Pharmacy,
Department of Pharmaceutical Sciences
Cellular and Molecular Oncology
In this proposed study we will apply the state-of-the-art technology of whole genome sequencing to advance our understanding of arsenic as a co-carcinogen when combined with another DNA damaging insult such as UVR. Our extensive and compelling experimental evidence support the hypothesis that arsenic enhances skin carcinogenesis by disrupting the zinc finger function of the key DNA repair protein XPA, which in turn, results in deficient nucleotide excision repair leading to greater accumulation of somatic mutations. Over the past 20 years, my research group has been working on investigating the molecular mechanisms of metal toxicity and carcinogenesis, particularly that of arsenic and chromium. Our research have made several key findings that are relevant to the mechanistic foundations of this proposal, including identification of XPA zinc finger motif and other C3H1 or C4 zinc fingers as direct targets for interaction with arsenic and zinc reversal of arsenic actions at the chemical, cellular and animal level. A particular strength of our research is the utilization of multidisciplinary approaches, using techniques ranging from chemical to biochemical to biophysical, and from molecular and cellular level to animal models, to answer the specific biological questions. Our research efforts have been continuously supported by numerous NIH grants since 1995, leading to the publications of over 200 peer-reviewed papers in the area of oxidative stress and metal carcinogenesis.
Dr. Hudson and I have been having a highly effective and productive collaboration over the past 15 years. Our respective expertise in cell and molecular biology (Hudson) and metal chemistry (Liu) complements each other perfectly well. This research partnership has been very successful with multiple collaborative NIH R01 awards, and more than 30 joint publications. In the current application, we team up with Dr. Ludmil Alexandrov from UC San Diego, a pioneer and world leader in whole genome sequencing and mutational signature research, to study the mutational signatures obtained from single versus combined exposures with or without zinc intervention in a defined experimental cell system and in vivo skin carcinogenesis. Our initial collaboration, supported by the University of New Mexico Comprehensive Cancer Center, has already generated the exciting and intriguing preliminary results on arsenic enhancement of UV-induced mutations that are presented in the proposal.