DDX54 regulates transcriptome dynamics during DNA damage response.
DDX54 regulates transcriptome dynamics during DNA damage response.
复制标题
DOI：
10.1101/gr.218438.116
复制
发表时间：
2017-08
期刊：
影响因子：
7
通讯作者：
Landthaler M
中科院分区：
文献类型：
--
作者：
Milek M;Imami K;Mukherjee N;Bortoli F;Zinnall U;Hazapis O;Trahan C;Oeffinger M;Heyd F;Ohler U;Selbach M;Landthaler M
细胞对遗传毒性应激的反应是由特征明确的DNA监测途径网络介导的。转录后基因调控网络对DNA损伤反应（DDR）的贡献尚未得到广泛研究。在这里，我们系统地确定了RNA结合蛋白的差异相互作用与多聚腺苷酸转录后，暴露于电离辐射（IR）的人乳腺癌细胞。有趣的是，超过260种蛋白质，包括许多核仁蛋白质，在IR暴露的细胞中显示出与poly（A）+ RNA的结合增加。DDX 54（一种候选的遗传毒性应激反应RNA解旋酶）的功能分析显示，该蛋白质是其靶IR诱导的前mRNA的剪接功效所需的即刻至早期DDR调节剂。在IR暴露后，DDX 54通过增加与具有弱受体剪接位点的内含子的明确定义的前mRNA类的相互作用以及通过U2 snRNP和剪接体B复合物的组分内的蛋白质-蛋白质接触起作用，从而导致其靶转录物的较低内含子保留和较高加工速率。由于DDX 54促进暴露于IR后的存活，因此其表达和/或突变率可能影响DDR相关的病理。我们的工作表明，复员方案中可能涉及的许多未定性的限制性商业惯例具有相关性。
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.
登录
查看更多内容
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
4.3
作者：
Corvelo A;Hallegger M;Smith CW;Eyras E
通讯作者：
Eyras E
影响因子：
10.5
作者：
Boutz PL;Bhutkar A;Sharp PA
通讯作者：
Sharp PA
影响因子：
16
作者：
Beli, Petra;Lukashchuk, Natalia;Wagner, Sebastian A.;Weinert, Brian T.;Olsen, Jesper V.;Baskcomb, Linda;Mann, Matthias;Jackson, Stephen P.;Choudhary, Chunaram
通讯作者：
Choudhary, Chunaram
影响因子：
9.2
作者：
Andersen, JS;Lyon, CE;Lamond, AI
通讯作者：
Lamond, AI