KANSAS CITY, MO. (Dec. 16, 2004) - Thomas Kusch, Ph.D., a Senior Research Associate at the Stowers Institute working with Investigator Jerry Workman, Ph.D., has identified a histone-modifying complex from Drosophila melanogaster (fruit flies), which facilitates DNA double-strand repair by locally increasing DNA accessibility at sites of damage.
The findings are available in the Dec. 17 issue of Science.
"DNA double strand breaks are regarded as one of the primary causes of cancer," says Kusch. "While there are natural mechanisms within an organism to detect and repair these breaks, factors involved in DNA damage repair must first bypass histones. Histones are proteins that condense DNA and protect it from mechanical and other stresses, but also make DNA rather inaccessible."
Multiprotein complexes are able to modify or mobilize histones to overcome the obstacle imposed by histones, and it has long been assumed that such complexes must act in concert with DNA repair enzymes at sites of DNA double-strand breaks. It was unclear, however, which types of histone-modifying complexes do this job, how they target sites of DNA double-strand breaks, or how they remodel histones to assist DNA repair.
The complex acting in this process turned out to be identical to an already identified human complex that contained a number of candidate tumor suppressors including a specialized histone variant called H2A.X/v. H2A.X/v itself becomes phosphorylated by a DNA damage- recognizing factor in the proximity of DNA double-strand breaks. This finding raised the possibility that the complex, which was called the dTip60 complex, might specifically be attracted by phospho-H2A.X/v, and thus targeted to sites of DNA damage.
Dr. Kusch was able to demonstrate that this complex recognizes phospho-H2A.X/v when present on DNA. It then modifies the phospho-histone by acetylating it, which facilitates its removal from DNA. In a second step, the dTip60 complex removes phospho-H2A.X/v and replaces it with an unmodified form of the histone. Taken together, Dr. Kusch's findings show that the dTip60 complex increases DNA accessibility at sites of damage for optimal DNA repair and at the same time removes the DNA damage-marker phospho-H2A.X/v to signal the cell that this defect has been successfully repaired.
"These findings answer fundamental questions about DNA double-strand break repair," says Robb Krumlauf, Ph.D., Scientific Director of the Stowers Institute. "They may ultimately help to formulate new strategies of cancer therapy. Dr. Kusch's research with Dr. Workman is another example of the ground-breaking work being conducted here at the Stowers Institute."
Dr. Kusch will continue to focus on the dTip60 complex in his future research. In addition to Dr. Workman, he was joined in this project by Stowers colleagues Laurence Florens, Ph.D., Managing Director of Proteomics; Selene Swanson, Research Specialist I; Susan Abmayr, Ph.D., Associate Investigator; Mike Washburn,, Ph.D., Director of the Proteomics Center; and colleagues at Scripps Research Institute and the Wadsworth Center.
About the Institute
Situated on a 10-acre campus in the heart of Kansas City, Missouri, the Stowers Institute for Medical Research conducts research on the fundamental processes of cellular life. Through basic research of the highest quality, the Stowers Institute seeks insights that will lead to more effective ways of preventing and curing disease. The Institute was founded in 1994 by Jim and Virginia Stowers, two cancer survivors who have dedicated their fortune to supporting the basic research that will provide long-term solutions to gene-based diseases.
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