Abstract
The tRNA methyltransferase NSUN2 delays replicative senescence by regulating the translation of CDK1 and CDKN1B mRNAs. However, whether NSUN2 influences premature cellular senescence remains untested. Here we show that NSUN2 methylates SHC mRNA in vitro and in cells, thereby enhancing the translation of the three SHC proteins, p66SHC, p52SHC, and p46SHC. Our results further show that the elevation of SHC expression by NSUN2-mediated mRNA methylation increased the levels of ROS, activated p38MAPK, thereby accelerating oxidative stress- and high-glucose-induced senescence of human vascular endothelial cells (HUVEC). Our findings highlight the critical impact of NSUN2-mediated mRNA methylation in promoting premature senescence.
Keywords:
Gerotarget; HUVEC; NSUN2; SHC mRNA methylation; premature senescence; translational regulation.
MeSH terms
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Blotting, Western
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CDC2 Protein Kinase / genetics
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CDC2 Protein Kinase / metabolism
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Cells, Cultured
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Cellular Senescence / genetics*
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Cyclin-Dependent Kinase Inhibitor p27 / genetics
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Cyclin-Dependent Kinase Inhibitor p27 / metabolism
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Gene Expression Regulation*
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HCT116 Cells
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Human Umbilical Vein Endothelial Cells / cytology
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Human Umbilical Vein Endothelial Cells / enzymology
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Human Umbilical Vein Endothelial Cells / metabolism*
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Humans
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Methylation
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Methyltransferases / genetics*
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Methyltransferases / metabolism
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Oxidative Stress*
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RNA Interference
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Reactive Oxygen Species / metabolism
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Src Homology 2 Domain-Containing, Transforming Protein 1 / genetics
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Src Homology 2 Domain-Containing, Transforming Protein 1 / metabolism
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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RNA, Messenger
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Reactive Oxygen Species
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SHC1 protein, human
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Src Homology 2 Domain-Containing, Transforming Protein 1
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Cyclin-Dependent Kinase Inhibitor p27
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Methyltransferases
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NSUN2 protein, human
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CDC2 Protein Kinase
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CDK1 protein, human
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p38 Mitogen-Activated Protein Kinases