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KAP1, a Novel Substrate for PIKK Family Members, Colocalizes with Numerous Damage Response Factors at DNA Lesions

The Wistar Institute, Philadelphia, Pennsylvania

Requests for reprints: Frank J. Rauscher III, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104. Phone: 215-898-0995; Fax: 215-898-3929; E-mail: rauscher{at}wistar.org.

The DNA damage response requires a coordinated nucleo-cytoplasmic cascade of events, which ultimately converge on damaged DNA packaged in chromatin. Few connections between the proteins that remodel chromatin and the proteins that mediate this damage response have been shown. We have investigated the DNA damage–induced phosphorylation of the KRAB-ZFP–associated protein 1 (KAP1), the dedicated corepressor for Krüppel-associated box (KRAB) zinc finger protein (ZFP) proteins. We show that KAP1 is rapidly phosphorylated following DNA damage by members of the phosphatidylinositol-3 kinase–like family of kinases. This phosphorylation occurs at a single amino acid residue that is conserved from mice to humans and is located adjacent to the bromodomain, suggesting that it may regulate chromatin recognition by that module. Phosphorylated KAP1 rapidly localizes to sites of DNA strand breaks in the nucleus in response to ionizing radiation. This discovery provides a novel link between chromatin-mediated transcriptional repression and the recognition/repair of DNA, which must be accomplished by the cellular DNA damage response. (Cancer Res 2006; 66(24): 11594-9)

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