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The BARD1 C-terminal domain structure and interactions with polyadenylation factor CstF-50.

The BARD1 N-terminal RING domain binds BRCA1 while the BARD1 C-terminal ankyrin and tandem BRCT repeat domains bind CstF-50 to modulate mRNA processing and RNAP II stability in response to DNA damage. Here we characterize the BARD1 structural biochemistry responsible for CstF-50 binding. The crystal structure of the BARD1 BRCT domain uncovers a degenerate phosphopeptide binding pocket lacking the key arginine required for phosphopeptide interactions in other BRCT proteins. Small angle X-ray scattering together with limited proteolysis results indicates that ankyrin and BRCT domains are linked by a flexible tether and do not adopt a fixed orientation relative to one another. Protein pull-down experiments utilizing a series of purified BARD1 deletion mutants indicate that interactions between the CstF-50 WD-40 domain and BARD1 involve the ankyrin-BRCT linker but do not require ankyrin or BRCT domains. The structural plasticity imparted by the ANK-BRCT linker helps to explain the regulated assembly of different protein BARD1 complexes with distinct functions in DNA damage signaling including BARD1-dependent induction of apoptosis plus p53 stabilization and interactions. BARD1 architecture and plasticity imparted by the ANK-BRCT linker are suitable to allow the BARD1 C-terminus to act as a hub with multiple binding sites to integrate diverse DNA damage signals directly to RNA polymerase.

Pubmed ID: 18842000


  • Edwards RA
  • Lee MS
  • Tsutakawa SE
  • Williams RS
  • Nazeer I
  • Kleiman FE
  • Tainer JA
  • Glover JN



Publication Data

November 4, 2008

Associated Grants

  • Agency: NCI NIH HHS, Id: CA92584

Mesh Terms

  • Binding Sites
  • Cleavage Stimulation Factor
  • Crystallography, X-Ray
  • DNA Damage
  • Humans
  • In Vitro Techniques
  • Models, Molecular
  • Polyadenylation
  • Protein Interaction Domains and Motifs
  • Protein Structure, Tertiary
  • RNA Processing, Post-Transcriptional
  • Recombinant Fusion Proteins
  • Scattering, Small Angle
  • Tumor Suppressor Proteins
  • Ubiquitin-Protein Ligases
  • X-Ray Diffraction