New Understanding Of DNA Repair May Pave Way To Cancer Treatments

Ze'ev Ronai, Ph.D., Director of the Institute's Signal Transduction Program, and his colleagues found that the protein ATF2 ("Activating Transcription Factor-2") is activated by a protein kinase called ATM ("Ataxia-Telangiectasia Mutated), which stimulates DNA repair. ATF2's role in regulating expression of proteins that control cell cycle and programmed cell death is well established. The current study is the first to demonstrate ATF2's role in DNA repair, an intracellular process that prevents formation of genetic mutations, including those that lead to cancer.

"This is the first time we've seen a protein which has been implicated in gene regulation possess an independent function--in DNA repair--while both functions are uncoupled from one another," said Ronai. Dr. Ronai's laboratory has been studying ATF2 with the goal of understanding its role in regulation of cell cycle and programmed cell death. These studies evolved from the finding that ATF2 has an important role in the development and progression of melanoma tumors. Inhibition of ATF2 was found to sensitize melanoma to various treatments, both in tissue culture and in animal models.

"Melanoma is usually resistant to chemotherapy, but we found that by inhibiting ATF2, it became more sensitive to treatment," Ronai said. Consequently, his laboratory developed a small peptide that interferes with ATF2 function, efficiently blocking melanoma growth in mouse models. Ongoing studies are devoted to screening for compounds that mimic the peptide's actions and to allow for further development of the peptide toward clinical assessment.

"Until our recent studies, we were certain that the mechanism by which ATF2 affects melanoma growth was primarily through its established function in the regulation of proteins important in cell cycle and cell death control. We were therefore most surprised to find an uncoupled function for the same protein," said Ronai.

The finding of ATF2's novel function in DNA repair was serendipitous. As Shoichi Takahashi, a postgraduate researcher, was testing for the changes in ATF2 in human cancers, he "lost the signal" for ATF2. "Later," Dr. Ronai said, "we did experiments that showed the signal was lost because a protein kinase, ATM, modified ATF2 enough to interfere with detection of the ATF2 signal. Soon, work performed by Anindita Bhoumik confirmed that ATF2 is regulated by ATM and that this regulation is central to the cell's ability to initiate DNA repair processes following ionizing irradiation or other exposures that cause breaks in DNA. A likely way in which ATF2 works is to halt the cell's cycle to allow repair of damaged DNA before such damage becomes permanent."

Ronai and his colleagues are now determining how molecules like ATF2 can balance their dual roles. "High doses of radiation, as well as changes that take place in cancer and pathologic situations, can activate both functions of ATF2, which is expected to disturb the otherwise conserved balance between its role in gene regulation and the DNA damage response. We need to find out which of the two functions is more dominant under these circumstances in order to devise ways to regain the proper balance," he said.

The Ronai lab's work on ATF2 was started at Mount Sinai School of Medicine in New York City, from which Dr Ronai and his colleagues recently relocated to the Burnham Institute. This study was carried out in collaboration with Wolfgang Breitweiser and Nic Jones of the Paterson Institute for Cancer Research, Manchester, England, and Yosef Shiloh, of Tel Aviv University, Israel. The study was supported by a grant from the National Institutes of Health.

The Burnham Institute, founded in 1976, is an independent not-for-profit biomedical research institution dedicated to advancing the frontiers of scientific knowledge and providing the foundation for tomorrow's medical therapies. The Institute is home to three major centers: the original Cancer Center, the Del E. Webb Neuroscience and Aging Center established in 1999, and the Infectious and Inflammatory Disease Center dedicated in 2004. Since 1981, the Institute's Cancer Center has earned the prestigious designation as a Non-comprehensive Cancer Center by the National Cancer Institute. Discoveries by Burnham scientists have contributed to the development of new drugs for Alzheimer's disease, heart disease and several forms of cancer. Today the Burnham Institute employs over 700, including more than 550 scientists. The majority of the Institute's funding derives from federal sources, but private philanthropic support is essential to continuing bold and innovative research. For additional information about the Institute and ways to support the research efforts of the Institute, visit www.burnham.org.