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

Abstract

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.

• Authors: Yi Shi, Ze Liu, Qian Zhang, Ingrid Vallee, Zhongying Mo, Shuji Kishi, Xiang-Lei Yang
• Journal: PLoS biology (PLoS Biol) Vol. 18 Issue 12 Pg. e3000991 (12 2020) ISSN: 1545-7885 [Electronic] United States
• PMID: 33351793 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inducing Agents
• Hypoxia-Inducible Factor 1, alpha Subunit
• Transcription Factors
• Vascular Endothelial Growth Factor A
• Zebrafish Proteins
• ATM protein, human
• ATR protein, human
• ATR protein, zebrafish
• Ataxia Telangiectasia Mutated Proteins
• Serine-tRNA Ligase

Topics

• Angiogenesis Inducing Agents
• Animals
• Animals, Genetically Modified
• Ataxia Telangiectasia (genetics)
• Ataxia Telangiectasia Mutated Proteins (genetics, metabolism, physiology)
• Cell Line
• Female
• HEK293 Cells
• Humans
• Hypoxia (metabolism, physiopathology)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Mice
• Mice, Nude
• Neovascularization, Pathologic (genetics)
• Phosphorylation
• Serine-tRNA Ligase (metabolism, physiology)
• Transcription Factors (metabolism)
• Vascular Endothelial Growth Factor A (genetics, metabolism)
• Xenograft Model Antitumor Assays (methods)
• Zebrafish (metabolism)
• Zebrafish Proteins (metabolism)