title: Systematic screening reveals a role for BRCA1 in the response to transcription-associated DNA damage.
abstract: BRCA1 is a breast and ovarian tumor suppressor. Given its numerous incompletely understood functions and the possibility that more exist, we performed complementary systematic screens in search of new BRCA1 protein-interacting partners. New BRCA1 functions and/or a better understanding of existing ones were sought. Among the new interacting proteins identified, genetic interactions were detected between BRCA1 and four of the interactors: TONSL, SETX, TCEANC, and TCEA2. Genetic interactions were also detected between BRCA1 and certain interactors of TONSL, including both members of the FACT complex. From these results, a new BRCA1 function in the response to transcription-associated DNA damage was detected. Specifically, new roles for BRCA1 in the restart of transcription after UV damage and in preventing or repairing damage caused by stabilized R loops were identified. These roles are likely carried out together with some of the newly identified interactors. This new function may be important in BRCA1 tumor suppression, since the expression of several interactors, including some of the above-noted transcription proteins, is repeatedly aberrant in both breast and ovarian cancers.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Hill
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA;
authors.forename: Thomas
authors.initials: T
authors.lastname: Rolland
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA; Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA;
authors.forename: Guillaume
authors.initials: G
authors.lastname: Adelmant
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA;
authors.forename: Xianfang
authors.initials: X
authors.lastname: Xia
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA;
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Owen
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA;
authors.forename: Amélie
authors.initials: A
authors.lastname: Dricot
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; The Broad Institute, Cambridge, Massachusetts 02142, USA;
authors.forename: Travis I
authors.initials: TI
authors.lastname: Zack
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA;
authors.forename: Nidhi
authors.initials: N
authors.lastname: Sahni
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; Département de Virologie, Unité de Génétique Moléculaire des Virus à ARN, Institut Pasteur, F-75015 Paris, France; UMR3569, Centre National de la Recherche Scientifique, F-75015 Paris, France; Unité de Génétique Moléculaire des Virus à ARN, Université Paris Diderot, F-75015 Paris, France;
authors.forename: Yves
authors.initials: Y
authors.lastname: Jacob
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA;
authors.forename: Tong
authors.initials: T
authors.lastname: Hao
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Kristine M
authors.initials: KM
authors.lastname: McKinney
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Allison P
authors.initials: AP
authors.lastname: Clark
authors.affiliation: Molecular Pathology Unit, Center for Computational and Integrative Biology, Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA; Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Deepak
authors.initials: D
authors.lastname: Reyon
authors.affiliation: Molecular Pathology Unit, Center for Computational and Integrative Biology, Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA; Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Shengdar Q
authors.initials: SQ
authors.lastname: Tsai
authors.affiliation: Molecular Pathology Unit, Center for Computational and Integrative Biology, Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA; Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: J Keith
authors.initials: JK
authors.lastname: Joung
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; The Broad Institute, Cambridge, Massachusetts 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA; Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA;
authors.forename: Jarrod A
authors.initials: JA
authors.lastname: Marto
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA;
authors.forename: Marc
authors.initials: M
authors.lastname: Vidal
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA;
authors.forename: Suzanne
authors.initials: S
authors.lastname: Gaudet
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA;
authors.forename: David E
authors.initials: DE
authors.lastname: Hill
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA; david_livingston@dfci.harvard.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Livingston
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping; D014158:Transcription, Genetic / Q000235:genetics*; D014466:Ultraviolet Rays
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D016328:NF-kappa B; C093394:TONSL protein, human
keywords: BRCA1 interaction screening; DNA damage; transcription