Genes Involved in DNA Double-Strand Break Repair: Implications for Breast Cancer
Abstract
Both double-strand break repair and V(D)J 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. V(D)J 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 1997
- Accession Number
- ADA341403
Entities
People
- Gilbert Chu
Organizations
- Stanford University