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

J. Vohhodina; E.M. Barros; A.L. Savage; F.G. Liberante; L. Manti; P. Bankhead; N. Cosgrove; A.F. Madden; D.P. Harkin; K.I. Savage

doi:10.1093/nar/gkx1046

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

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

J. Vohhodina, E.M. Barros, A.L. Savage, F.G. Liberante, L. Manti, P. Bankhead, N. Cosgrove, A.F. Madden, D.P. Harkin and K.I. Savage

Nucleic Acids Research, Vol.45(22), pp.12816-12833

2017

DOI: https://doi.org/10.1093/nar/gkx1046

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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.

Details

Title: The RNA processing factors THRAP3 and BCLAF1 promote the DNA damage response through selective mRNA splicing and nuclear export
Authors/Creators: J. Vohhodina (Author/Creator)
E.M. Barros (Author/Creator)
A.L. Savage (Author/Creator)
F.G. Liberante (Author/Creator)
L. Manti (Author/Creator)
P. Bankhead (Author/Creator)
N. Cosgrove (Author/Creator)
A.F. Madden (Author/Creator)
D.P. Harkin (Author/Creator)
K.I. Savage (Author/Creator)
Publication Details: Nucleic Acids Research, Vol.45(22), pp.12816-12833
Publisher: Oxford University Press
Identifiers: 991005545250507891
Copyright: © The Author(s) 2017
Murdoch Affiliation: Murdoch University
Language: English
Resource Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.54 Molecular & Cell Biology - Genetics; 1.54.469 Alternative Splicing
Web Of Science research areas: Biochemistry & Molecular Biology
ESI research areas: Biology & Biochemistry