Effect of DNA damage on a BRCA1 complex.
The tumour-suppressor protein BRCA1 mediates its biological functions by interacting with cellular factors such as the CtIP polypeptide, a substrate for the ATM (for 'ataxia telangiectasia mutated') protein kinase. Li et al. report that the BRCA1-CtIP interaction is disrupted by ionizing radiation and by other genotoxic stresses that induce phosphorylation of CtIP by ATM kinase, and that this dissociation of the BRCA1-CtIP complex in turn modulates the transcription of DNA-damage-response genes. We have shown that the BRCA1-binding domain of CtIP (amino-acid residues 133-369) is distal to the sites that are phosphorylated by ATM kinase (residues S664 and S745). We now show that the BRCA1-CtIP complex is stable in irradiated cells, and that the phosphorylated isoforms of CtIP that are induced by ionizing radiation still interact in vivo with BRCA1. We conclude that disruption of the BRCA1-CtIP complex cannot account for induction of DNA-damage-response genes in the way proposed by Li et al.
Wu-Baer
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F
Institute of Cancer Genetics and Department of Pathology, Columbia University College of Physicians and Surgeons, 1150 St Nicholas Avenue, New York, New York 10032, USA.
Baer
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R
D000911:Antibodies, Monoclonal; D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein / Q000378:metabolism* / Q000528:radiation effects; D002352:Carrier Proteins / Q000378:metabolism* / Q000528:radiation effects; D018797:Cell Cycle Proteins; D002461:Cell Line, Transformed; D004247:DNA / Q000378:metabolism / Q000528:radiation effects; D004249:DNA Damage / Q000235:genetics; D004268:DNA-Binding Proteins; D004706:Endodeoxyribonucleases; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism* / Q000528:radiation effects; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism / Q000528:radiation effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D014466:Ultraviolet Rays
D000911:Antibodies, Monoclonal; D019313:BRCA1 Protein; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D025521:Tumor Suppressor Proteins; D004247:DNA; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D004706:Endodeoxyribonucleases; C410741:RBBP8 protein, human