MCB Faculty Research
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Kathleen Dixon Ph.D. Rochester 1970 Contact Information |
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Research Interests:
Cellular Response to DNA Damage
Research
Our research focuses on cellular responses to DNA damage. Preservation of the integrity of the genome is essential to survival of individual cells and the whole organism. Genetic mutations can lead to disruption of the normal pattern of development and to cancer. A wide variety of environmental agents (e.g., UV radiation, toxic chemicals, etc.) as well as intrinsic metabolic processes (e.g., oxidative stress) can damage DNA leading to mutations. We are interested in understanding the mechanisms by which organisms respond to DNA damage to prevent mutations and cell death. We are using tools of molecular biology and biochemistry combined with genetic approaches to address these questions. Although much of our work is carried out in cultured mammalian cells and cell-free systems, we also make use of other experimental systems, such as yeast and transgenic mice.
Currently, we are investigating the nature of the DNA damage signal that activates protein kinases (especially ATM and ATR) that phosphorylate proteins involved in DNA replication and DNA repair, including the single-stranded DNA binding protein RPA, the MRE11/RAD50/NBS1 complex, and the BLM protein. ??We showed that the signal from UV damage is the blockage of the DNA replication complex at sites of damage. It is thought that similar blockage occurs occasionally during normal DNA replication and a failure to properly overcome the blockage is a basis for certain human genomic instability syndromes. DNA damage-induced phosphorylation of RPA causes changes in RPA function which may lead to inhibition of its role in DNA replication and enhancement of its role in DNA repair. Further work in this area will involve proteomic approaches to investigating alterations in protein partnering associated with phosphorylation of RPA.
We are also interested in understanding more about the mechanisms of action of two known human carcinogens, chromium and arsenic. We have used mutagenesis assay systems from yeast, mammalian cells and transgenic mice to investigate the molecular mechanisms of chromate mutagenesis. These studies have shown that chromate is highly mutagenic and causes oxidative-type DNA damage. Chromate induces mutations in all three assay systems and the mutagenic activity depends on the redox state of the cells and the ability of the cells to repair oxidative DNA damage. In contrast, arsenite does not appear to be mutagenic by itself, but it amplifies mutagenesis by other agents that damage DNA (e.g., UV radiation, methylmethane sulfonate, etc.). Our studies show that arsenite interferes with the removal of UV-induced DNA damage causing enhanced DNA damage signaling and prolonged cell cycle checkpoints. In addition, arsenite alone causes an accumulation of cells in mitosis. Future work will focus on understanding the molecular mechanism by which arsenite interferes with removal of DNA damage.
Selected Publications