Key result
Abrogation of a newly identified DNA damage-induced BRCA1 protein complex containing BCLAF1 results in sensitivity to DNA damage, defective DNA repair, and genomic instability.
Identifies a novel BRCA1-mRNA splicing complex essential for DNA repair and genomic stability, providing insights into cellular responses to DNA damage and potential cancer mechanisms.
Extends BRCA1 repair biology in models; leaves open therapeutic relevance for genomic instability or cancer pending human validation.
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.
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Savage et al. (2014) studied Breast and ovarian cancers. Abrogation of BRCA1-mRNA splicing complex was evaluated on DNA damage sensitivity, DNA repair, and genomic instability. Abrogation of a newly identified DNA damage-induced BRCA1 protein complex containing BCLAF1 results in sensitivity to DNA damage, defective DNA repair, and genomic instability.