BRCA1 interacts with acetyl-CoA carboxylase through its tandem of BRCT domains.
Germ-line alterations in BRCA1 are associated with an increased susceptibility to breast and ovarian cancer. BRCA1 is a 220-kDa protein that contains a tandem of two BRCA1 C-Terminal (BRCT) domains. Among missense and nonsense BRCA1 mutations responsible for family breast cancer, some are located into the BRCT tandem of BRCA1 coding sequence. In an attempt to understand how BRCT is critical for BRCA1 function, we search for partners of this BRCT tandem of BRCA1. Using a glutathione-S-transferase (GST) pull-down assay with murine cells, we isolated only one major BRCA1-interacting protein, further identified as Acetyl Coenzyme A (CoA) Carboxylase alpha (ACCA). We showed that this interaction is conserved through murine and human species. We also delineated the minimum interacting region as being the whole tandem of BRCT domains. We demonstrated that BRCA1 interacts in vitro and in vivo with ACCA. This interaction is completely abolished by five distinct germline BRCA1 deleterious mutations affecting the BRCT tandem of BRCA1. Interestingly, ACCA originally known as a rate-limiting enzyme for fatty acids biosynthesis, has been recently shown to be over-expressed in breast cancers and considered as a potential target for anti-neoplastic therapy. Furthermore, our observation is making a bridge between the genetic factors involved in susceptibility to breast and ovarian cancers, and environmental factors such as nutrition considered as key elements in the etiology of those cancers.
D016475:3T3 Cells; D000103:Acetyl-CoA Carboxylase / Q000737:chemistry* / Q000378:metabolism; D020816:Amino Acid Motifs; D000818:Animals; D019313:BRCA1 Protein / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics; D019398:Genes, BRCA1; D006801:Humans; D051379:Mice; D009154:Mutation; D014407:Tumor Cells, Cultured
D019313:BRCA1 Protein; D000103:Acetyl-CoA Carboxylase