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Defining mutagenesis pathways in tobacco-related cancer

Institution: Scripps Research Institute
Investigator(s): Bryan O'Neill, BA Chemistry
Award Cycle: 2005 (Cycle 14) Grant #: 14DT-0137 Award: $58,993
Subject Area: Cancer
Award Type: Dissertation Awards

Initial Award Abstract
The greatest difficulty in fighting cancer is that all cancers are distinct from one another, and thus require different treatments. However, all forms of cancer, including those that are tobacco-related, do begin the same way, with the mutation of DNA. Conventionally, it has been thought that mutations, and therefore cancer, typically begin with errors made by the enzymes that maintain the genome. We now know that this is not correct: in order for mutation to occur in microorganisms (bacteria and yeast), as well as mammals (mice and humans), the cell must play an active role. The notion that cells mutate themselves in response to stress is not simply of academic interest, but rather, this idea identifies a new, potentially revolutionary, approach to cancer prevention and treatment – namely, the prevention of mutation.

This proposal seeks to understand the process of mutation through the use of mutagens that mimic the effect of many of the carcinogens found in tobacco. As such, this research will define how tobacco-related cancers evolve. In addition, the proteins identified during the course of this work will be exciting new drug-targets to prevent and treat tobacco-related cancer. The main objectives of the research proposed herein are to identify all of the genes involved in the process of mutagenesis and organize them into groups based on experimentally determined properties. To date, only a few components of these pathways are known, thus, a more comprehensive understanding of mutation will aid in future therapeutic strategies.

Using yeast as a model organism, whole-genome screens have been initiated to identify mutants that have a reduced capacity to mutate. The proposed research seeks to continue this work by studying mutants selected from these screens, with the aim of identifying those genes that are most important to mutation. Emphasis will be placed on those genes with human homologs, since evolutionarily conserved genes often code for proteins with identical functions.

This proposal combines the new view of mutation and cancer prevention with the innovative and powerful genetic tools available in yeast. With a thorough understanding of the proteins that mediate mutation in this model organism, we will begin unraveling the molecular origins of mutation in human cells, with an emphasis on mechanism and how mutation might be inhibited. This research will therefore lay the foundations for subsequent projects directed at understanding mutation in human cells, with profound implications for human health.