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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • BRCA1 Protein / metabolism*
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism
  • Cell Survival / radiation effects
  • DNA Damage
  • DNA Repair Enzymes / genetics
  • DNA Repair Enzymes / metabolism
  • DNA Repair*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Exodeoxyribonucleases / genetics
  • Exodeoxyribonucleases / metabolism
  • Fanconi Anemia Complementation Group Proteins / genetics
  • Fanconi Anemia Complementation Group Proteins / metabolism
  • Genome, Human
  • Genomic Instability*
  • HEK293 Cells
  • Humans
  • Phosphorylation
  • Protein Processing, Post-Translational
  • RNA Splicing
  • RNA, Messenger / metabolism*
  • Radiation Tolerance
  • Repressor Proteins / metabolism
  • Tumor Suppressor Proteins / metabolism

Substances

  • ATRIP protein, human
  • Adaptor Proteins, Signal Transducing
  • BACH1 protein, human
  • BCLAF1 protein, human
  • BRCA1 Protein
  • BRCA1 protein, human
  • Basic-Leucine Zipper Transcription Factors
  • DNA-Binding Proteins
  • Fanconi Anemia Complementation Group Proteins
  • RNA, Messenger
  • Repressor Proteins
  • Tumor Suppressor Proteins
  • EXO1 protein, human
  • Exodeoxyribonucleases
  • DNA Repair Enzymes