title: Identification of a BRCA1-mRNA splicing complex required for efficient DNA repair and maintenance of genomic stability.
abstract: Mutations within BRCA1 predispose carriers to a high risk of breast and ovarian cancers. BRCA1 functions to maintain genomic stability through the assembly of multiple protein complexes involved in DNA repair, cell-cycle arrest, and transcriptional regulation. Here, we report the identification of a DNA damage-induced BRCA1 protein complex containing BCLAF1 and other key components of the mRNA-splicing machinery. In response to DNA damage, this complex regulates pre-mRNA splicing of a number of genes involved in DNA damage signaling and repair, thereby promoting the stability of these transcripts/proteins. Further, we show that abrogation of this complex results in sensitivity to DNA damage, defective DNA repair, and genomic instability. Interestingly, mutations in a number of proteins found within this complex have been identified in numerous cancer types. These data suggest that regulation of splicing by the BRCA1-mRNA splicing complex plays an important role in the cellular response to DNA damage.
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK. Electronic address: k.savage@qub.ac.uk.
authors.forename: Kienan I
authors.initials: KI
authors.lastname: Savage
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK.
authors.forename: Julia J
authors.initials: JJ
authors.lastname: Gorski
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK.
authors.forename: Eliana M
authors.initials: EM
authors.lastname: Barros
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK.
authors.forename: Gareth W
authors.initials: GW
authors.lastname: Irwin
authors.affiliation: Dipartimento di Fisiche, Università Federico II di Napoli, Complesso Universitario di Monte S. Angelo, Naples 80126, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Manti
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Powell
authors.affiliation: Leukaemia and Lymphoma Research Molecular Haematology Unit, Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pellagatti
authors.affiliation: The Gurdon Institute and Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
authors.forename: Natalia
authors.initials: N
authors.lastname: Lukashchuk
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: McCance
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK; Department of Pathology, Belfast Health and Social Care Trust, 274 Grosvenor Road, Belfast BT12 6BA, UK.
authors.forename: W Glenn
authors.initials: WG
authors.lastname: McCluggage
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK; Radiation Dosimetry Group, National Physical Laboratory, Hampton Road, Teddington TW11 0LW, UK.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Schettino
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK.
authors.forename: Manuel
authors.initials: M
authors.lastname: Salto-Tellez
authors.affiliation: Leukaemia and Lymphoma Research Molecular Haematology Unit, Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Boultwood
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, 4059 Brisbane, Australia.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Richard
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK.
authors.forename: Simon S
authors.initials: SS
authors.lastname: McDade
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK. Electronic address: d.harkin@qub.ac.uk.
authors.forename: D Paul
authors.initials: DP
authors.lastname: Harkin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D019313:BRCA1 Protein / Q000378:metabolism*; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005090:Exodeoxyribonucleases / Q000235:genetics / Q000378:metabolism; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics / Q000378:metabolism; D015894:Genome, Human; D042822:Genomic Instability; D057809:HEK293 Cells; D006801:Humans; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism*; D011836:Radiation Tolerance; D012097:Repressor Proteins / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C521194:ATRIP protein, human; D048868:Adaptor Proteins, Signal Transducing; C102108:BACH1 protein, human; C119386:BCLAF1 protein, human; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D051856:Fanconi Anemia Complementation Group Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; C114331:EXO1 protein, human; D005090:Exodeoxyribonucleases; D045643:DNA Repair Enzymes
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