Grant: Operating Grant

The outcome of drug therapy can vary significantly from one individual to the next. Studies of model systems, such as breast and lung cancer cell lines, have shown that variability in drug responses can originate at the level of individual cells, even under stringently controlled laboratory conditions. Understanding the causes of this variability is important because it can reduce effectiveness of drug treatment, and facilitate the development of drug resistance. The proposed research will identify causes of high cell-to-cell variability in drug-induced transcription of genes encoding the enzyme ribonucleotide reductase (RNR) among genetically identical budding yeast cells. This organism is used extensively in health-related biomedical research because it shares many important genes and pathways with humans, including those involved in DNA replication and repair. Moreover, increased expression of the RNR enzyme is required for DNA damage repair in all organisms, and the enzyme is the direct target of drugs used in established and experimental cancer therapies. Our preliminary investigations demonstrate that variability in single-cell responses to DNA damage and certain anti-cancer drugs involves the suppression of RNR gene transcription in some cells, but not in others. Moreover, our studies implicate multiple conserved genes and pathways involved in cell cycle control and the stress response. Correspondingly, we anticipate that the proposed research will provide new important insights into the mechanisms that cells use to integrate information about DNA damage, cell growth and stress, and enable new research to improve the efficacy of disease therapies, including those that target the RNR enzyme.