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DDX54 regulates transcriptome dynamics during DNA damage response

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Official URL:https://doi.org/10.1101/gr.218438.116
PubMed:View item in PubMed
Creators Name:Milek, M. and Imami, K. and Mukherjee, N. and De Bortoli, F. and Zinnall, U. and Hazapis, O. and Trahan, C. and Oeffinger, M. and Heyd, F. and Ohler, U. and Selbach, M. and Landthaler, M.
Journal Title:Genome Research
Journal Abbreviation:Genome Res
Date:8 June 2017
Keywords:DNA Damage Response, RNA-Binding Proteins, MRNA Interactome Capture, RNA Helicase DDX54, Intron Retention, Pre-MRNA Splicing, Transcriptome Dynamics
Abstract:The cellular response to genotoxic stress is mediated by a well-characterized network of DNA surveillance pathways. The contribution of posttranscriptional 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 which 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. Since 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.
ISSN:1088-9051
Publisher:Cold Spring Harbor Laboratory Press (U.S.A.)
Item Type:Article

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