Structure of the 53BP1 BRCT region bound to p53 and its comparison to the Brca1 BRCT structure Journal Article

Authors: Joo, W. S.; Jeffrey, P. D.; Cantor, S. B.; Finnin, M. S.; Livingston, D. M.; Pavletich, N. P.
Article Title: Structure of the 53BP1 BRCT region bound to p53 and its comparison to the Brca1 BRCT structure
Abstract: Brca1 C-terminal (BRCT) domains are a common protein-protein interaction motif in proteins involved in the DNA damage response and DNA repair. The DNA-damage response protein 53BP1 has two BRCT domains that bind to the DNA-binding domain of p53. The 53BP1 tandem-BRCT region is homologous to the tandem-BRCT region of Brca1, which is involved in double-strand break repair and homologous recombination and which binds BACH1, a member of the DEAH helicase family. Here we report the structures of a human 53BP1-p53 complex and of the rat Brca1 BRCT repeats. The 53BP1-p53 structure shows that the two BRCT repeats are arranged tandemly and pack extensively through an interface that also involves the inter-repeat linker. The first BRCT repeat and the linker together bind p53 on a region that overlaps with the DNA-binding surface of p53 and involves p53 residues that are mutated in cancer and are important for DNA binding. Comparison with the structure of the tandem-BRCT region of Brca1 shows a remarkable conservation of the repeat arrangement and of the inter-BRCT repeat interface. Analysis of human BRCA1 tumor-derived mutations and conservation identifies a potential protein-binding site that we show through mutagenesis is involved in BACH1 binding. The BACH1-binding region of Brca1 consists of a unique insertion in the first BRCT repeat and the inter-repeat linker and is analogous to the region of 53BP1 that binds p53.
Keywords: protein domain; protein analysis; animals; dna damage; dna repair; protein protein interaction; brca1 protein; protein p53; dna strand breakage; genetic recombination; amino acid sequence; molecular sequence data; sequence homology, amino acid; intracellular signaling peptides and proteins; carrier proteins; phosphoproteins; tumor suppressor protein p53; models, molecular; rats; helicase; protein structure; protein family; brca1; p53; brct domain; bach1; humans; human; priority journal; article; insertion sequences; 53bp1
Journal Title: Genes and Development
Volume: 16
Issue: 5
ISSN: 0890-9369
Publisher: Cold Spring Harbor Laboratory Press  
Date Published: 2002-03-01
Start Page: 583
End Page: 593
Language: English
DOI: 10.1101/gad.959202
PUBMED: 11877378
PROVIDER: scopus
PMCID: PMC155350
Notes: Export Date: 14 November 2014 -- Source: Scopus
Citation Impact
MSK Authors
  1. Philip D Jeffrey
    30 Jeffrey
  2. Michael S Finnin
    4 Finnin
  3. Woo S Joo
    4 Joo