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Mol Cell. 2014 May 8;54(3):445-59. doi: 10.1016/j.molcel.2014.03.021. Epub 2014 Apr 17.

Identification of a BRCA1-mRNA splicing complex required for efficient DNA repair and maintenance of genomic stability.

Author information

1
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.
2
Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK.
3
Dipartimento di Fisiche, Università Federico II di Napoli, Complesso Universitario di Monte S. Angelo, Naples 80126, Italy.
4
Leukaemia and Lymphoma Research Molecular Haematology Unit, Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, Oxford OX3 9DU, UK.
5
The Gurdon Institute and Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
6
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.
7
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.
8
Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, 4059 Brisbane, Australia.
9
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.

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.

PMID:
24746700
PMCID:
PMC4017265
DOI:
10.1016/j.molcel.2014.03.021
[Indexed for MEDLINE]
Free PMC Article
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