title: tRNA synthetase counteracts c-Myc to develop functional vasculature.
abstract: 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.
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, United States Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States.
authors.forename: Yi
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, United States Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, United States Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, United States Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States.
authors.forename: Guangsen
authors.initials: G
authors.lastname: Fu
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, United States Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States.
authors.forename: Zhongying
authors.initials: Z
authors.lastname: Mo
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, United States Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States.
authors.forename: George S
authors.initials: GS
authors.lastname: Wang
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, United States.
authors.forename: Shuji
authors.initials: S
authors.lastname: Kishi
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, United States Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States xlyang@scripps.edu.
authors.forename: Xiang-Lei
authors.initials: XL
authors.lastname: Yang
mesh_terms: D000595:Amino Acid Sequence; D043925:Angiogenesis Inducing Agents / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D044127:Epigenesis, Genetic; D005260:Female; D020868:Gene Silencing; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011487:Protein Conformation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012714:Serine-tRNA Ligase / Q000235:genetics* / Q000494:pharmacology; D056565:Sirtuin 2 / Q000235:genetics / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish
chemical_list: D043925:Angiogenesis Inducing Agents; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D056565:Sirtuin 2; D012714:Serine-tRNA Ligase
keywords: SIRT2; VEGFA; angiogenesis; c-Myc; seryl-tRNA synthetase; vasculature