title: KAP1, a novel substrate for PIKK family members, colocalizes with numerous damage response factors at DNA lesions.
abstract: 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.
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: White
authors.forename: Dmitri
authors.initials: D
authors.lastname: Negorev
authors.forename: Hongzhuang
authors.initials: H
authors.lastname: Peng
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Ivanov
authors.forename: Gerd G
authors.initials: GG
authors.lastname: Maul
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Rauscher
mesh_terms: D002455:Cell Division; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003470:Culture Media; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019398:Genes, BRCA1; D006801:Humans; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D013379:Substrate Specificity; D000076183:Tripartite Motif-Containing Protein 28
chemical_list: D003470:Culture Media; D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D010768:Phosphoserine; C101116:TRIM28 protein, human; D000076183:Tripartite Motif-Containing Protein 28