mC 修饰在 HIV-1 转录本中的添加调控病毒基因表达。
Epitranscriptomic Addition of mC to HIV-1 Transcripts Regulates Viral Gene Expression.
机构信息
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
出版信息
Cell Host Microbe. 2019 Aug 14;26(2):217-227.e6. doi: 10.1016/j.chom.2019.07.005.
How the covalent modification of mRNA ribonucleotides, termed epitranscriptomic modifications, alters mRNA function remains unclear. One issue has been the difficulty of quantifying these modifications. Using purified HIV-1 genomic RNA, we show that this RNA bears more epitranscriptomic modifications than the average cellular mRNA, with 5-methylcytosine (mC) and 2'O-methyl modifications being particularly prevalent. The methyltransferase NSUN2 serves as the primary writer for mC on HIV-1 RNAs. NSUN2 inactivation inhibits not only mC addition to HIV-1 transcripts but also viral replication. This inhibition results from reduced HIV-1 protein, but not mRNA, expression, which in turn correlates with reduced ribosome binding to viral mRNAs. In addition, loss of mC dysregulates the alternative splicing of viral RNAs. These data identify mC as a post-transcriptional regulator of both splicing and function of HIV-1 mRNA, thereby affecting directly viral gene expression.
mRNA 核糖核苷酸的共价修饰（称为转录后修饰）如何改变 mRNA 的功能尚不清楚。一个问题一直是难以定量这些修饰。使用纯化的 HIV-1 基因组 RNA，我们表明，这种 RNA 带有比平均细胞 mRNA 更多的转录后修饰，其中 5-甲基胞嘧啶 (mC) 和 2'O-甲基修饰特别普遍。甲基转移酶 NSUN2 是 HIV-1 RNA 上 mC 的主要写入器。NSUN2 失活不仅抑制 HIV-1 转录物中 mC 的添加，还抑制病毒复制。这种抑制作用源于 HIV-1 蛋白表达减少，但 mRNA 表达减少，这反过来又与病毒 mRNAs 与核糖体结合减少相关。此外，mC 的缺失会扰乱病毒 RNA 的可变剪接。这些数据表明 mC 是 HIV-1 mRNA 剪接和功能的转录后调节剂，从而直接影响病毒基因表达。
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