Author/Editor		Milek, Miha; Imami, Koshi; Mukherjee, Neelanjan; De Bortoli, Francesca; Zinnall, Ulrike; Hazapis, Orsalia; Trahan, Christian; Oeffinger, Marlene; Heyd, Florian; Ohler, Uwe; Selbach, Matthias; Landthaler, Markus
Title		DDX54 regulates transcriptome dynamics during DNA damage response
Type		članek
Vol. and No.		Letnik 27, št. 8
Publication year		2017
Volume		str. 1344-1359
ISSN		1088-9051 - Genome research
Language		eng
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.
Keywords		DDX54 transkriptna dinamika RNA-vezavni protein DDX54 transcriptome dynamics RNA-binding protein