tRNA synthetase counteracts c-Myc to develop functional vasculature

eLife

Guangsen Fu¹  Xiaoling Xu¹  George S Wang¹  Xiang-Lei Yang¹  Yi Shi²  Qian Zhang²  Shuji Kishi²  Zhongying Mo² 

[1]Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States

[2]Department of Chemical Physiology, The Scripps Research Institute, La Jolla, United States

关键词: seryl-tRNA synthetase;    c-Myc;    VEGFA;    SIRT2;    angiogenesis;    vasculature;   

DOI  :  10.7554/eLife.02349

来源: DOAJ

【 摘 要 】

Recent studies suggested an essential role for seryl-tRNA synthetase (SerRS) in vascular development. This role is specific to SerRS among all tRNA synthetases and is independent of its well-known aminoacylation function in protein synthesis. A unique nucleus-directing domain, added at the invertebrate-to-vertebrate transition, confers this novel non-translational activity of SerRS. Previous studies showed that SerRS, in some unknown way, controls VEGFA expression to prevent vascular over-expansion. Using in vitro, cell and animal experiments, we show here that SerRS intervenes by antagonizing c-Myc, the major transcription factor promoting VEGFA expression, through a tandem mechanism. First, by direct head-to-head competition, nuclear-localized SerRS blocks c-Myc from binding to the VEGFA promoter. Second, DNA-bound SerRS recruits the SIRT2 histone deacetylase to erase prior c-Myc-promoted histone acetylation. Thus, vertebrate SerRS and c-Myc is a pair of ‘Yin-Yang’ transcriptional regulator for proper development of a functional vasculature. Our results also discover an anti-angiogenic activity for SIRT2.

【 授权许可】

Unknown