PRMT5 regulates IRES-dependent translation via methylation of hnRNP A1.
PRMT5 regulates IRES-dependent translation via methylation of hnRNP A1.
复制标题
DOI：
10.1093/nar/gkw1367
复制
发表时间：
2017-05-05
影响因子：
14.9
通讯作者：
Bedford MT
中科院分区：
文献类型：
--
作者：
Gao G;Dhar S;Bedford MT
II型精氨酸甲基转移酶PRMT 5负责组蛋白的对称二甲基化以产生H3 R8 me 2s和H4 R3 me 2s标记，其与转录的抑制相关。然而，据报道，许多基因（MEP 50，CCND 1，MYC，HIF 1a，MTIF和CDKN 1B）的蛋白质水平因PRMT 5的丢失而下调，而它们的mRNA水平保持不变，这与PRMT 5作为转录抑制因子的作用是违反直觉的。我们注意到大多数受PRMT 5调控的基因在转录后水平表达含有内部核糖体进入位点（IRES）的mRNA。使用IRES依赖的报告系统，我们建立了PRMT 5促进含IRES基因的一个子集的翻译。异质核核糖核蛋白，hnRNP A1，是一种IRES反式作用因子（ITAF），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被PRMT 5在两个残基R218和R225上甲基化，这种甲基化促进了hnRNP A1与IRES RNA的相互作用，以促进IRES依赖性翻译。这项研究定义了PRMT 5调节细胞蛋白水平的新作用，这超出了PRMT 5作为转录和剪接调节因子的已知功能。
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.