tRNA synthetase counteracts c-Myc to develop functional vasculature

• Published in: eLife 2014-06, Vol.3, p.e02349-e02349
• Main Authors: Shi, Yi, Xu, Xiaoling, Zhang, Qian, Fu, Guangsen, Mo, Zhongying, Wang, George S, Kishi, Shuji, Yang, Xiang-Lei
• Format: Article
• Language: English
• Subjects: Acetylation; Amino Acid Sequence; Aminoacylation; Angiogenesis; Angiogenesis Inducing Agents - pharmacology; Animal research; Animals; c-Myc; c-Myc protein; Cell Biology; Cell Line; Deoxyribonucleic acid; Developmental Biology and Stem Cells; DNA; Embryos; Epigenesis, Genetic; Female; Gene expression; Gene Silencing; HEK293 Cells; Histone deacetylase; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Localization; Male; Molecular Sequence Data; Mutagenesis; Mutation; Myc protein; Promoter Regions, Genetic; Protein biosynthesis; Protein Conformation; Protein synthesis; Proteins; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Research centers; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Serine-tRNA ligase; Serine-tRNA Ligase - genetics; Serine-tRNA Ligase - pharmacology; seryl-tRNA synthetase; SIRT2; Sirtuin 2 - genetics; Sirtuin 2 - pharmacology; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; vasculature; VEGFA; Vertebrates; Zebrafish
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.02349

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.DOI: http://dx.doi.org/10.7554/eLife.02349.001.