Phosphorylation of seryl-tRNA synthetase by ATM/ATR is essential for hypoxia-induced angiogenesis

• Published in: PLoS biology 2020-12, Vol.18 (12), p.e3000991-e3000991
• Main Authors: Shi, Yi, Liu, Ze, Zhang, Qian, Vallee, Ingrid, Mo, Zhongying, Kishi, Shuji, Yang, Xiang-Lei
• Format: Article
• Language: English
• Subjects: Analysis; Angiogenesis; Angiogenesis Inducing Agents; Animals; Animals, Genetically Modified; Antibodies; Ataxia; Ataxia telangiectasia; Ataxia Telangiectasia - genetics; Ataxia Telangiectasia Mutated Proteins - genetics; Ataxia Telangiectasia Mutated Proteins - metabolism; Ataxia Telangiectasia Mutated Proteins - physiology; Biology and Life Sciences; c-Myc protein; Cell Line; Colon; Colon cancer; Deoxyribonucleic acid; DNA; DNA damage; Enzymes; Female; Gene expression; Genetic aspects; HEK293 Cells; Homeostasis; Humans; Hypoxia; Hypoxia - metabolism; Hypoxia - physiopathology; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Ischemia; Kinases; Labeling; Medicine and Health Sciences; Methods; Mice; Mice, Nude; Molecular modelling; Myc protein; Neovascularization; Neovascularization, Pathologic - genetics; Phosphorylation; Physical Sciences; Physiological aspects; Proteins; Regulators; Research and Analysis Methods; Serine-tRNA ligase; Serine-tRNA Ligase - metabolism; Serine-tRNA Ligase - physiology; Transcription factors; Transcription Factors - metabolism; tRNA; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Vertebrates; Xenograft Model Antitumor Assays - methods; Xenografts; Xenotransplantation; Zebrafish - metabolism; Zebrafish Proteins - metabolism
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.3000991

Hypoxia-induced angiogenesis maintains tissue oxygen supply and protects against ischemia but also enhances tumor progression and malignancy. This is mediated through activation of transcription factors like hypoxia-inducible factor 1 (HIF-1) and c-Myc, yet the impact of hypoxia on negative regulators of angiogenesis is unknown. During vascular development, seryl-tRNA synthetase (SerRS) regulates angiogenesis through a novel mechanism by counteracting c-Myc and transcriptionally repressing vascular endothelial growth factor A (VEGFA) expression. Here, we reveal that the transcriptional repressor role of SerRS is inactivated under hypoxia through phosphorylation by ataxia telangiectasia mutated (ATM) and ataxia telangiectasia mutated and RAD3-related (ATR) at Ser101 and Ser241 to attenuate its DNA binding capacity. In zebrafish, SerRSS101D/S241D, a phosphorylation-mimicry mutant, cannot suppress VEGFA expression to support normal vascular development. Moreover, expression of SerRSS101A/S241A, a phosphorylation-deficient and constitutively active mutant, prevents hypoxia-induced binding of c-Myc and HIF-1 to the VEGFA promoter, and activation of VEGFA expression. Consistently, SerRSS101A/S241A strongly inhibits normal and tumor-derived angiogenesis in mice. Therefore, we reveal a key step regulating hypoxic angiogenesis and highlight the importance of nuclear SerRS in post-developmental angiogenesis regulation in addition to vascular development. The role of nuclear SerRS in inhibiting both c-Myc and HIF-1 may provide therapeutic opportunities to correct dysregulation of angiogenesis in pathological settings.