title: The BRCA2 activation domain associates with and is phosphorylated by a cellular protein kinase.
abstract: A substantial proportion of familial breast cancers have mutations within the BRCA2 gene. The product of this gene has been implicated in DNA repair and in the regulation of transcription. We have previously identified at the amino-terminus of BRCA2 a transcriptional activation domain whose importance is highlighted by the presence of predisposing mutations and in-frame deletions in breast cancer families. This activation domain shows sequence similarity to a region of c-Jun which has been defined as a binding site for the c-Jun N-terminal kinase. Here, we show that the analogous region in BRCA2 is also a binding site for a cellular kinase, although this kinase is distinct from JNK. The BRCA2 associated enzyme is able to phosphorylate residues within the BRCA2 activation domain. Consistent with this observation, we find that the activation domain of BRCA2 is phosphorylated in vivo. Our results indicate that the BRCA2 activation domain possesses a binding site for a kinase that may regulate BRCA2 activity by phosphorylation.
authors.affiliation: Wellcome/CRC Institute and Department of Pathology, Cambridge University, Tennis Court Road, Cambridge, CB2 1QR, UK.
authors.forename: J
authors.initials: J
authors.lastname: Milner
authors.forename: F
authors.initials: F
authors.lastname: Fuks
authors.forename: L
authors.initials: L
authors.lastname: Hughes-Davies
authors.forename: T
authors.initials: T
authors.lastname: Kouzarides
mesh_terms: D000595:Amino Acid Sequence; D024682:BRCA2 Protein; D001665:Binding Sites; D004789:Enzyme Activation; D005091:Exons; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000528:radiation effects; D011233:Precipitin Tests; D011494:Protein Kinases / Q000302:isolation & purification / Q000378:metabolism* / Q000528:radiation effects; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014466:Ultraviolet Rays
chemical_list: D024682:BRCA2 Protein; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; D005982:Glutathione Transferase; D011494:Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases