The RNA processing factors THRAP3 and BCLAF1 promote the DNA damage response through selective mRNA splicing and nuclear export

Jekaterina Vohhodina, Eliana M Barros, Abigail L Savage, Fabio G Liberante, Lorenzo Manti, Peter Bankhead, Nicola Cosgrove, Angelina F Madden, D Paul Harkin, Kienan I Savage

Research output: Contribution to journalArticlepeer-review

Abstract

mRNA splicing and export plays a key role in the regulation of gene expression, with recent evidence suggesting an additional layer of regulation of gene expression and cellular function through the selective splicing and export of genes within specific pathways. Here we describe a role for the RNA processing factors THRAP3 and BCLAF1 in the regulation of the cellular DNA damage response (DDR) pathway, a key pathway involved in the maintenance of genomic stability and the prevention of oncogenic transformation. We show that loss of THRAP3 and/or BCLAF1 leads to sensitivity to DNA damaging agents, defective DNA repair and genomic instability. Additionally, we demonstrate that this phenotype can be at least partially explained by the role of THRAP3 and BCLAF1 in the selective mRNA splicing and export of transcripts encoding key DDR proteins, including the ATM kinase. Moreover, we show that cancer associated mutations within THRAP3 result in deregulated processing of THRAP3/BCLAF1-regulated transcripts and consequently defective DNA repair. Taken together, these results suggest that THRAP3 and BCLAF1 mutant tumors may be promising targets for DNA damaging chemotherapy.

Original languageEnglish
Pages (from-to)12816-12833
Number of pages18
JournalNucleic Acids Research
Volume45
Issue number22
DOIs
Publication statusPublished - 15 Dec 2017

Keywords

  • Active Transport, Cell Nucleus/genetics
  • Ataxia Telangiectasia Mutated Proteins/genetics
  • Cell Line, Tumor
  • DNA Damage
  • DNA-Binding Proteins/genetics
  • Gene Expression Profiling/methods
  • HEK293 Cells
  • Humans
  • In Situ Hybridization, Fluorescence
  • Microscopy, Fluorescence
  • Mutation
  • RNA Interference
  • RNA Splicing
  • Repressor Proteins/genetics
  • Transcription Factors/genetics
  • Tumor Suppressor Proteins/genetics

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