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Stowers researcher publishes DNA double-strand break repair discovery in Science

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.
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Contact: Marie Jennings
mfj@stowers-institute.org
816-926-4015
Stowers Institute for Medical Research
16-Dec-2004


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