title: Structure of BRCA1-BRCT/Abraxas Complex Reveals Phosphorylation-Dependent BRCT Dimerization at DNA Damage Sites.
abstract: BRCA1 accumulation at DNA damage sites is an important step for its function in the DNA damage response and in DNA repair. BRCA1-BRCT domains bind to proteins containing the phosphorylated serine-proline-x-phenylalanine (pSPxF) motif including Abraxas, Bach1/FancJ, and CtIP. In this study, we demonstrate that ionizing radiation (IR)-induces ATM-dependent phosphorylation of serine 404 (S404) next to the pSPxF motif. Crystal structures of BRCT/Abraxas show that phosphorylation of S404 is important for extensive interactions through the N-terminal sequence outside the pSPxF motif and leads to formation of a stable dimer. Mutation of S404 leads to deficiency in BRCA1 accumulation at DNA damage sites and cellular sensitivity to IR. In addition, two germline mutations of BRCA1 are found to disrupt the dimer interface and dimer formation. Thus, we demonstrate a mechanism involving IR-induced phosphorylation and dimerization of the BRCT/Abraxas complex for regulating Abraxas-mediated recruitment of BRCA1 in response to IR.
authors.affiliation: Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, CB2 1GA Cambridge, UK.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Genetics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Genes and Development Program, The University of Texas Graduate School of Biomedical Sciences at Houston, 6767 Bertner Avenue, Houston, TX 77030, USA.
authors.forename: Atanu
authors.initials: A
authors.lastname: Paul
authors.affiliation: Department of Genetics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Su
authors.affiliation: Department of Chemistry, Physical and Theoretical Chemistry Laboratory, University of Oxford, South Parks Road, OX1 3QZ Oxford, UK.
authors.forename: Shahid
authors.initials: S
authors.lastname: Mehmood
authors.affiliation: Department of Radiation Oncology, Robert Wood Johnson Medical School, Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA.
authors.forename: Tzeh Keong
authors.initials: TK
authors.lastname: Foo
authors.affiliation: Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, CB2 1GA Cambridge, UK.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ochi
authors.affiliation: Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, CB2 1GA Cambridge, UK.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Bunting
authors.affiliation: Department of Radiation Oncology, Robert Wood Johnson Medical School, Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Xia
authors.affiliation: Department of Chemistry, Physical and Theoretical Chemistry Laboratory, University of Oxford, South Parks Road, OX1 3QZ Oxford, UK.
authors.forename: Carol V
authors.initials: CV
authors.lastname: Robinson
authors.affiliation: Department of Genetics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Genes and Development Program, The University of Texas Graduate School of Biomedical Sciences at Houston, 6767 Bertner Avenue, Houston, TX 77030, USA. Electronic address: bwang3@mdanderson.org.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, CB2 1GA Cambridge, UK. Electronic address: tom@cryst.bioc.cam.ac.uk.
authors.forename: Tom L
authors.initials: TL
authors.lastname: Blundell
mesh_terms: D000595:Amino Acid Sequence; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D019313:BRCA1 Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D018360:Crystallography, X-Ray; D004249:DNA Damage; D018095:Germ-Line Mutation; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D034622:RNA Interference; D012694:Serine; D014162:Transfection
chemical_list: C520310:ABRAXAS1 protein, human; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D002352:Carrier Proteins; D012694:Serine; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins