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New understanding of DNA repair may pave way to cancer treatments

La Jolla, Calif. A Burnham Institute study has found that a protein known for its role in gene regulation has another important function, that of initiating DNA repair. The study, published in the May 27th edition of Molecular Cell, points to new targets for treatment of cancer.

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 whic
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Contact: Nancy Beddingfield
nbeddingfield@burnham.org
858-646-3146
Burnham Institute
26-May-2005


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