Structure of the 53BP1 BRCT region bound to p53 and its comparison to the Brca1 BRCT structure.
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.
Joo
Woo S
WS
Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Jeffrey
Philip D
PD
Cantor
Sharon B
SB
Finnin
Michael S
MS
Livingston
David M
DM
Pavletich
Nikola P
NP
D000595:Amino Acid Sequence; D000818:Animals; D019313:BRCA1 Protein / Q000737:chemistry*; D002352:Carrier Proteins / Q000737:chemistry*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010750:Phosphoproteins; D051381:Rats; D017386:Sequence Homology, Amino Acid; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry*; D000071857:Tumor Suppressor p53-Binding Protein 1
D019313:BRCA1 Protein; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; C498301:TP53BP1 protein, human; D016159:Tumor Suppressor Protein p53; D000071857:Tumor Suppressor p53-Binding Protein 1