title: TopBP1 contains a transcriptional activation domain suppressed by two adjacent BRCT domains.
abstract: TopBP1 has eight BRCT [BRCA1 (breast-cancer susceptibility gene 1) C-terminus] domains and is involved in initiating DNA replication, and DNA damage checkpoint signalling and repair. Several BRCT-domain-containing proteins involved in mediating DNA repair have transcriptional regulatory domains, and as demonstrated for BRCA1 these regulatory domains are important in mediating the functions of these proteins. These transcriptional regulatory processes involve modification of chromatin, and recent evidence has clearly demonstrated that the ability to modify chromatin plays an important role in regulating DNA damage signalling and repair. Here we report the identification of a TopBP1 transcriptional activation domain that is rich in hydrophobic residues, interspersed with acidic amino acids, characteristics that are typical of transcriptional activation domains identified previously. Two adjacent repressor domains encoded by BRCT2 and BRCT5 silence this activator and experiments suggest that these repressors actively recruit repressor complexes. Both the activator and BRCT2 repressor domains function in yeast. The present study identifies several chromatin modification domains encoded by TopBP1, and the implications of these findings are discussed in the context of the DNA damage response and the understanding of TopBP1 function.
authors.affiliation: Institute of Comparative Medicine, Division of Pathological Sciences, University of Glasgow Faculty of Veterinary Medicine, Garscube Estate, Switchback Road, Glasgow G61 1QH, Scotland UK.
authors.forename: Roni H G
authors.initials: RH
authors.lastname: Wright
authors.forename: Edward S
authors.initials: ES
authors.lastname: Dornan
authors.forename: Mary M
authors.initials: MM
authors.lastname: Donaldson
authors.forename: Iain M
authors.initials: IM
authors.lastname: Morgan
mesh_terms: D019313:BRCA1 Protein / Q000737:chemistry / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D004268:DNA-Binding Proteins; D020868:Gene Silencing; D006801:Humans; D009687:Nuclear Proteins; D017434:Protein Structure, Tertiary; D014158:Transcription, Genetic
chemical_list: D019313:BRCA1 Protein; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C110513:TOPBP1 protein, human