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



Vohhodina, Jekaterina, Barros, Eliana M, Savage, Abigail L ORCID: 0000-0002-2231-9800, Liberante, Fabio G, Manti, Lorenzo, Bankhead, Peter, Cosgrove, Nicola, Madden, Angelina F, Harkin, D Paul and Savage, Kienan I
(2017) The RNA processing factors THRAP3 and BCLAF1 promote the DNA damage response through selective mRNA splicing and nuclear export. Nucleic Acids Research, 45 (22). pp. 12816-12833.

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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.

Item Type: Article
Uncontrolled Keywords: Cell Line, Tumor, Humans, DNA Damage, DNA-Binding Proteins, Tumor Suppressor Proteins, Transcription Factors, Repressor Proteins, Microscopy, Fluorescence, In Situ Hybridization, Fluorescence, Gene Expression Profiling, RNA Interference, RNA Splicing, Active Transport, Cell Nucleus, Mutation, HEK293 Cells, Ataxia Telangiectasia Mutated Proteins
Depositing User: Symplectic Admin
Date Deposited: 05 Jun 2019 09:14
Last Modified: 19 Jan 2023 00:41
DOI: 10.1093/nar/gkx1046
Open Access URL: https://doi.org/10.1093/nar/gkx1046
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3044540