Identification of a BRCA1-mRNA Splicing Complex Required for Efficient DNA Repair and Maintenance of Genomic Stability

Kienan I. Savage*, Julia J. Gorski, Eliana M. Barros, Gareth W. Irwin, Lorenzo Manti, Alexander J. Powell, Andrea Pellagatti, Natalia Lukashchuk, Dennis J. McCance, W. Glenn McCluggage, Giuseppe Schettino, Manuel Salto-Tellez, Jacqueline Boultwood, Derek J. Richard , Simon S. McDade, D. Paul Harkin

*Corresponding author for this work

Research output: Contribution to journalArticle

85 Citations (Scopus)
249 Downloads (Pure)

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.
Original languageEnglish
Pages (from-to)445-459
Number of pages15
JournalMolecular Cell
Volume54
Issue number3
DOIs
Publication statusPublished - 08 May 2014

    Fingerprint

Keywords

  • BRCA1, DNA damage, genome stability, DNA repair, mRNA splicing

Cite this