Structural requirements for the BARD1 tumor suppressor in chromosomal stability and homology-directed DNA repair Journal Article

Authors: Laufer, M.; Nandula, S. V.; Modi, A. P.; Wang, S.; Jasin, M.; Murty, V. V. V. S.; Ludwig, T.; Baer, R.
Article Title: Structural requirements for the BARD1 tumor suppressor in chromosomal stability and homology-directed DNA repair
Abstract: The BRCA1 tumor suppressor exists as a heterodimeric complex with BARD1, and this complex is thought to mediate many of the functions ascribed to BRCA1, including its role in tumor suppression. The two proteins share a common structural organization that features an N-terminal RING domain and two C-terminal BRCT motifs, whereas BARD1 alone also contains three tandem ankyrin repeats. In normal cells, the BRCA1/ BARD1 heterodimer is believed to enhance chromosome stability by promoting homology-directed repair (HDR) of double strand DNA breaks. Here we have investigated the structural requirements for BARD1 in this process by complementation of Bard1-null mouse mammary carcinoma cells. Our results demonstrate that the ankyrin and BRCT motifs of BARD1 are each essential for both chromosome stability and HDR. Tandem BRCT motifs, including those found at the C terminus of BARD1, are known to form a phosphoprotein recognition module. Nonetheless, the HDR function of BARD1 was not perturbed by synthetic mutations predicted to ablate the phospho-recognition activity of its BRCT sequences, suggesting that some functions of the BRCT domains are not dependent on their ability to bind phosphorylated ligands. Also, cancer-associated missense mutations in the BRCT domains of BARD1 (e.g. C557S, Q564H, V695L, and S761N) have been observed in patients with breast, ovarian, and endometrial tumors. However, none of these was found to affect the HDR activity of BARD1, suggesting that any increased cancer risk conferred by these mutations is not because of defects in this repair mechanism. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.
Keywords: controlled study; protein phosphorylation; gene mutation; mutation, missense; nonhuman; protein domain; protein function; protein motif; proteins; animal cell; mouse; animals; mice; dna repair; amino acid substitution; carboxy terminal sequence; protein binding; risk factors; cell line, tumor; structure-activity relationship; brca1 protein; oncology; proteomics; dna; amino acid sequence; tumors; cancer cell; breast carcinoma; tumor suppressor proteins; dna breaks, double-stranded; phosphoproteins; ligands; chromosomal instability; multiprotein complexes; tumor suppressor; protein structure; sequence homology; tumor suppressor protein; ubiquitin-protein ligases; chromosomes; mammary neoplasms, animal; genetic complementation test; brca1 associated ring domain protein 1; ring finger domains; chromosomal stability; ankyrins
Journal Title: Journal of Biological Chemistry
Volume: 282
Issue: 47
ISSN: 0021-9258
Publisher: American Society for Biochemistry and Molecular Biology  
Date Published: 2007-11-23
Start Page: 34325
End Page: 34333
Language: English
DOI: 10.1074/jbc.M705198200
PUBMED: 17848578
PROVIDER: scopus
Notes: --- - "Cited By (since 1996): 6" - "Export Date: 17 November 2011" - "CODEN: JBCHA" - "Source: Scopus"
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MSK Authors
  1. Maria Jasin
    223 Jasin