Gao Guozhen, Dhar Surbhi, Bedford Mark T
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
Nucleic Acids Res. 2017 May 5;45(8):4359-4369. doi: 10.1093/nar/gkw1367.
The type II arginine methyltransferase PRMT5 is responsible for the symmetric dimethylation of histone to generate the H3R8me2s and H4R3me2s marks, which correlate with the repression of transcription. However, the protein level of a number of genes (MEP50, CCND1, MYC, HIF1a, MTIF and CDKN1B) are reported to be downregulated by the loss of PRMT5, while their mRNA levels remain unchanged, which is counterintuitive for PRMT5's proposed role as a transcription repressor. We noticed that the majority of the genes regulated by PRMT5, at the posttranscriptional level, express mRNA containing an internal ribosome entry site (IRES). Using an IRES-dependent reporter system, we established that PRMT5 facilitates the translation of a subset of IRES-containing genes. The heterogeneous nuclear ribonucleoprotein, hnRNP A1, is an IRES transacting factor (ITAF) that regulates the IRES-dependent translation of Cyclin D1 and c-Myc. We showed that hnRNP A1 is methylated by PRMT5 on two residues, R218 and R225, and that this methylation facilitates the interaction of hnRNP A1 with IRES RNA to promote IRES-dependent translation. This study defines a new role for PRMT5 regulation of cellular protein levels, which goes beyond the known functions of PRMT5 as a transcription and splicing regulator.
II型精氨酸甲基转移酶PRMT5负责组蛋白的对称二甲基化，以产生H3R8me2s和H4R3me2s标记，这些标记与转录抑制相关。然而，据报道，一些基因（MEP50、CCND1、MYC、HIF1a、MTIF和CDKN1B）的蛋白质水平会因PRMT5的缺失而下调，而它们的mRNA水平保持不变，这与PRMT5作为转录抑制因子的假定作用相悖。我们注意到，在转录后水平上，受PRMT5调控的大多数基因表达含有内部核糖体进入位点（IRES）的mRNA。使用IRES依赖性报告系统，我们证实PRMT5促进了一部分含IRES基因的翻译。异质性核核糖核蛋白hnRNP A1是一种IRES反式作用因子（ITAF），可调节细胞周期蛋白D1和c-Myc的IRES依赖性翻译。我们发现hnRNP A1在两个位点R218和R225上被PRMT5甲基化，这种甲基化促进了hnRNP A1与IRES RNA的相互作用，从而促进IRES依赖性翻译。这项研究确定了PRMT5在调节细胞蛋白质水平方面的新作用，这超出了PRMT5作为转录和剪接调节因子的已知功能。
