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Genome Res. 2017 Aug;27(8):1344-1359. doi: 10.1101/gr.218438.116. Epub 2017 Jun 8.

DDX54 regulates transcriptome dynamics during DNA damage response.

Author information

1
Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin Institute for Medical Systems Biology, 13125 Berlin, Germany.
2
Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin, Institute of Chemistry and Biochemistry, Laboratory of RNA Biochemistry, 14195 Berlin, Germany.
3
Institut de Recherches Cliniques de Montréal, H2W 1R7 Montréal, Quebec, Canada.
4
Département de Biochimie, Faculté de Médecine, Université de Montréal, H3A 1A3 Montréal, Quebec, Canada.
5
Faculty of Medicine, Division of Experimental Medicine, McGill University, H3T 1J4 Montréal, Quebec, Canada.
6
Institute of Biology, Humboldt-Universität zu Berlin, 10115 Berlin, Germany.
7
Department of Computer Science, Humboldt-Universität zu Berlin, 10099 Berlin, Germany.
8
Charite-Universitätsmedizin Berlin, 10115 Berlin, Germany.
9
IRI Life Sciences, Institute of Biology, Humboldt-Universität zu Berlin, 10115 Berlin, Germany.

Abstract

The cellular response to genotoxic stress is mediated by a well-characterized network of DNA surveillance pathways. The contribution of post-transcriptional gene regulatory networks to the DNA damage response (DDR) has not been extensively studied. Here, we systematically identified RNA-binding proteins differentially interacting with polyadenylated transcripts upon exposure of human breast carcinoma cells to ionizing radiation (IR). Interestingly, more than 260 proteins, including many nucleolar proteins, showed increased binding to poly(A)+ RNA in IR-exposed cells. The functional analysis of DDX54, a candidate genotoxic stress responsive RNA helicase, revealed that this protein is an immediate-to-early DDR regulator required for the splicing efficacy of its target IR-induced pre-mRNAs. Upon IR exposure, DDX54 acts by increased interaction with a well-defined class of pre-mRNAs that harbor introns with weak acceptor splice sites, as well as by protein-protein contacts within components of U2 snRNP and spliceosomal B complex, resulting in lower intron retention and higher processing rates of its target transcripts. Because DDX54 promotes survival after exposure to IR, its expression and/or mutation rate may impact DDR-related pathologies. Our work indicates the relevance of many uncharacterized RBPs potentially involved in the DDR.

PMID:
28596291
PMCID:
PMC5538551
DOI:
10.1101/gr.218438.116
[Indexed for MEDLINE]
Free PMC Article

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