title: Transcriptional activities of the zinc finger protein Zac are differentially controlled by DNA binding.
abstract: Zac encodes a zinc finger protein that promotes apoptosis and cell cycle arrest and is maternally imprinted. Here, we show that Zac contains transactivation and repressor activities and that these transcriptional activities are differentially controlled by DNA binding. Zac transactivation mapped to two distinct domains. One of these contained multiple repeats of the peptide PLE, which behaved as an autonomous activation unit. More importantly, we identified two related high-affinity DNA-binding sites which were differentially bound by seven Zac C(2)H(2) zinc fingers. Zac bound as a monomer through zinc fingers 6 and 7 to the palindromic DNA element to confer transactivation. In contrast, binding as a monomer to one half-site of the repeat element turned Zac into a repressor. Conversely, Zac dimerization at properly spaced direct and reverse repeat elements enabled transactivation, which strictly correlated with DNA-dependent and -independent contacts of key residues within the recognition helix of zinc finger 7. The later ones support specific functional connections between Zac DNA binding and transcriptional-regulatory surfaces. Both classes of DNA elements were identified in a new Zac target gene and confirmed that the zinc fingers communicate with the transactivation function. Together, our data demonstrate a role for Zac as a transcription factor in addition to its role as coactivator for nuclear receptors and p53.
authors.affiliation: Molecular Neuroendocrinology, Max Planck Institute of Psychiatry, D-80804 Munich, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Hoffmann
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ciani
authors.forename: Joel
authors.initials: J
authors.lastname: Boeckardt
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.forename: Laurent
authors.initials: L
authors.lastname: Journot
authors.forename: Dietmar
authors.initials: D
authors.lastname: Spengler
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D016147:Genes, Tumor Suppressor; D006801:Humans; D007633:Keratins / Q000235:genetics; D008954:Models, Biological; D008969:Molecular Sequence Data; D005810:Multigene Family; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; C106464:PLAGL1 protein, human; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D007633:Keratins; D004247:DNA