Editors' ChoiceCancer

Mapping BRCT Interactions

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Science's STKE  06 Jan 2004:
Vol. 2004, Issue 214, pp. tw6
DOI: 10.1126/stke.2142004tw6

The BRCT (BRCA1 C-terminal) domain is an amino acid motif found in BRCA1, a tumor suppressor protein (mutations of which are associated with breast and ovarian cancer). This motif is also found in many other proteins implicated in regulating DNA damage and checkpoint responses. Recent research has identified the BRCT domain as a phosphoserine/phosphothreonine-dependent binding motif that may recruit proteins to sites phosphorylated by kinases activated in response to DNA damage [(see Editorial Guide and Sci. STKE, 2003, tw421 (2003)]. Rodriguez et al. used oriented phosphoserine-containing peptide libraries to analyze the binding specificity of the BRCT domains of BRCA1, MDC1 (a protein involved in DNA damage responses), BARD1 (whose mutation is associated with breast cancer), and DNA ligase IV. Fusion proteins containing tandem BRCT repeats from these proteins preferentially bound to distinct phosphoserine-containing peptides. The tandem BRCT domains of Rad9, a DNA repair protein from yeast, also bound phosphopeptides, which indicated that this interaction had arisen early in evolution. Mutational analysis of the BRCA1 BRCT-binding motif in the target BACH1 (BRCA1-associated carboxyl-terminal helicase 1) transfected into HeLa cells indicated that this motif was important for the G2/M checkpoint response to DNA damage. Database searches based on the consensus motifs identified potential targets of the various BRCT domain-containing proteins. These data further implicate the BRCT domain-containing proteins in the establishment of phosphorylation-dependent protein complexes involved in the DNA damage response.

M. Rodriguez, X. Yu, J. Chen, Z. Songyang, Phosphopeptide binding specificities of BRCA1 COOH-terminal (BRCT) domains. J. Biol. Chem. 278, 52914-52918 (2003). [Abstract] [Full Text]

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