title: Truncation mutations abolish chromatin-associated activities of adenomatous polyposis coli.
abstract: The adenomatous polyposis coli (APC) is a tumor suppressor whose loss of function leads to colon cancer. APC shuttles between the nucleus and cytoplasm, however its role in the nucleus remains elusive. We have found that nuclear APC specifically associates with transcriptionally active chromatin through structural elements located downstream to the region of frequent truncation mutations found in colorectal tumors. We show that a recombinant APC fragment comprising such elements associates in vivo with euchromatin and preferentially binds in vitro to acetylated histone H3. Induction of DNA double-strand breaks (DSB) stimulates accumulation of APC at the damaged DNA chromatin marked by histone H2AX and S139-phosphorylated histone H2AX. A nuclear complex containing the DNA-dependent protein kinase catalytic subunit (DNAPKcs) and APC associates with chromatin in response to DNA DSB. APC knockdown with siRNA decreased the rate of DNA DSB-induced S139 histone H2AX phosphorylation in cells expressing endogenous full-length APC, but not in colon cancer cells with its truncation mutants, whereas ectopic APC expression stimulated the H2AX phosphorylation regardless of the type of endogenous APC. Our data suggest that APC involves in the DSB DNA repair and that truncation mutations impair chromatin-associated functions of APC.
authors.affiliation: Department of Nuclear Signaling, Institute of Molecular and Cellular Biosciences, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: A P
authors.initials: AP
authors.lastname: Kouzmenko
authors.forename: K
authors.initials: K
authors.lastname: Takeyama
authors.forename: Y
authors.initials: Y
authors.lastname: Kawasaki
authors.forename: T
authors.initials: T
authors.lastname: Akiyama
authors.forename: S
authors.initials: S
authors.lastname: Kato
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000503:physiopathology*; D001665:Binding Sites; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D017491:Genes, APC; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D009154:Mutation; D015533:Transcriptional Activation
chemical_list: D002843:Chromatin; D051548:Histone Acetyltransferases