RNA methyltransferase NSUN2 promotes stress-induced HUVEC senescence

Xiaoyu Cai,Yuanyuan Hu,Bin Jiang,Chuan Chen,Wengong Wang,Lijun Pang,Han Hu,Junyue Xing,Te Liu,Yuhong Luo,Hao Tang,Zhenyun Liu,Myriam Gorospe

doi:10.18632/oncotarget.8087

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.

Highlights

The SHC family of proteins consists of three isoforms, p66SHC, p52SHC, and p46SHC, that arise through alternative initiation of translation [1]
P66SHC may play important roles in human cancer and aging, since elevation of p66SHC protein has been observed in primary human prostate tumors [5], in replicative senescence [6, 7], in middle-aged mice [8], as well as in cells exposed to oxidative stress and to short-wavelength ultraviolet irradiation (UVC) [9, 10]. p66SHC levels are regulated by enhanced protein turnover mediated by the tumor suppressor TP53 (p53) and by suppression of transcription following DNMT3bmediated methylation of the SHC promoter region [11, 12]
To test if SHC expression could be regulated by NSUN2-mediated mRNA methylation, we tested SHC protein levels in HeLa cells in which NSUN2 was overexpressed or silenced

Summary

Introduction

The SHC family of proteins consists of three isoforms, p66SHC, p52SHC, and p46SHC, that arise through alternative initiation of translation [1]. All three SHC isoforms were found to form a complex with Grb and functioned as “adaptor” proteins in the Ras signaling pathway. Unlike p52SHC and p46SHC, p66SHC contains a unique N-terminal collagen homology domain (CH2), which confers to p66SHC functions besides that of activator of the Ras signal pathway [2]. Phosphorylation of Ser, which is located at the CH2 domain, triggers ROS (reactive oxygen species) production, a critical function of p66SHC in determining the longevity of mammals [3, 4]. We showed that microRNA let-7 represses the translation of p66SHC in replicative senescence, the type of senescence that is triggered by the critical shortening of telomeres after a finite round of divisions [6]. Whether SHC expression influences cell senescence triggered by other factors was not studied

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Conclusion