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Genes Involved in DNA Double-Strand Break Repair: Implications for Breast Cancer

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Annual rept. 1 Oct 96-30 Sep 97

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Both double-strand break repair and VDJ recombination require DNA-dependent protein kinase DNA-PK, which consists of a subunit Ku that binds to DNA ends, and a 460 kDa catalytic subunit p460. Although previous reports suggested that DNA-PK is activated by the binding of Ku to DNA, we found conditions in which p460 was activated in the absence of Ku. Thus, p460 is a self-contained kinase that is activated by direct interaction with DNA. VDJ recombination is initiated by a cleavage reaction that nicks DNA and then forms a hairpin coding end and blunt signal end. To better understand the subsequent joining reaction, we measured the activation of DNA-PK by different DNA structures. Surprisingly, nicks and hairpin ends did not activate the kinase, even though hairpin coding ends require the intact kinase to be joined. To resolve this paradox, we hypothesize that hairpin end processing requires a trans phosphorylation by DNA-PK bound to co-generated signal ends. In fact, the activation of DNA-PK by open DNA ends leads to phosphorylation of p460 that follows second order kinetics and thus must occur in trans. These experiments have dissected early steps in repairing double-strand breaks induced by ionizing radiation, a critical risk factor for breast cancer.

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  • Biochemistry
  • Genetic Engineering and Molecular Biology
  • Anatomy and Physiology
  • Medicine and Medical Research

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