title: PARP1-driven poly-ADP-ribosylation regulates BRCA1 function in homologous recombination-mediated DNA repair.
abstract: BRCA1 promotes homologous recombination-mediated DNA repair (HRR). However, HRR must be tightly regulated to prevent illegitimate recombination. We previously found that BRCA1 HRR function is regulated by the RAP80 complex, but the mechanism was unclear. We have now observed that PARP1 interacts with and poly-ADP-ribosylates (aka PARsylates) BRCA1. PARsylation is directed at the BRCA1 DNA binding domain and downmodulates its function. Moreover, RAP80 contains a poly-ADP-ribose-interacting domain that binds PARsylated BRCA1 and helps to maintain the stability of PARP1-BRCA1-RAP80 complexes. BRCA1 PARsylation is a key step in BRCA1 HRR control. When BRCA1 PARsylation is defective, it gives rise to excessive HRR and manifestations of genome instability. BRCA1 PARsylation and/or RAP80 expression is defective in a subset of sporadic breast cancer cell lines and patient-derived tumor xenograft models. These observations are consistent with the possibility that such defects, when chronic, contribute to tumor development in BRCA1+/+ individuals.
  
  
  CONCLUSIONS
  We propose a model that describes how BRCA1 functions to both support and restrict HRR. BRCA1 PARsylation is a key event in this process, failure of which triggers hyper-recombination and chromosome instability. Thus, hyperfunctioning BRCA1 can elicit genomic abnormalities similar to those observed in the absence of certain BRCA1 functions.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Genetics, Harvard Medical School, Boston, Massachusetts. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Yiduo
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Genetics, Harvard Medical School, Boston, Massachusetts.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Petit
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts. Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Scott B
authors.initials: SB
authors.lastname: Ficarro
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Genetics, Harvard Medical School, Boston, Massachusetts.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Toomire
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: Anyong
authors.initials: A
authors.lastname: Xie
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Elgene
authors.initials: E
authors.lastname: Lim
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Shiliang A
authors.initials: SA
authors.lastname: Cao
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Eunyoung
authors.initials: E
authors.lastname: Park
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Eck
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: Ralph
authors.initials: R
authors.lastname: Scully
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Myles
authors.initials: M
authors.lastname: Brown
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts. Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Jarrod A
authors.initials: JA
authors.lastname: Marto
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Genetics, Harvard Medical School, Boston, Massachusetts. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. david_livingston@dfci.harvard.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Livingston
mesh_terms: D000595:Amino Acid Sequence; D019313:BRCA1 Protein / Q000737:chemistry / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002877:Chromosomes, Human; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins; D005260:Female; D015870:Gene Expression; D042822:Genomic Instability; D006367:HeLa Cells; D056488:Histone Chaperones; D059765:Homologous Recombination; D006801:Humans; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability; D021122:Protein Subunits / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D019313:BRCA1 Protein; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D010446:Peptide Fragments; D021122:Protein Subunits; C466234:UIMC1 protein, human; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases