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.

The Long-Noncoding RNA TUG1 Regulates Oxygen-Induced Retinal Neovascularization in Mice via MiR-299

“…One alternative is shRNA-mediated gene therapy, which has been shown to effectively reduce the number of treatments and shorten the treatment cycle. 40 – 44 In the current study, we suppressed VEGF expression using a single injection of shTUG1, resulting in significant reduction in pathological changes associated with retinal neovascularization in the OIR mouse model. This study therefore can provide a new concept regarding the treatment of ROP and also offers a potential treatment option for other retinal neovascular diseases.…”

Bladder Cancer‐Derived Small Extracellular Vesicles Promote Tumor Angiogenesis by Inducing HBP‐Related Metabolic Reprogramming and SerRS O‐GlcNAcylation in Endothelial Cells

“…For example, Shi and colleagues revealed that ATM/ATR‐mediated phosphorylation of SerRS at Ser101 and Ser241 decreased its DNA binding ability and thus attenuated hypoxia‐induced angiogenesis. [ 43 ] Moreover, a work by Fu suggested the negative role of SerRS in angiogenesis by forming the SerRS/YY1 complex, which, while competing with NFKB1, binds distal cis‐regulatory elements of the VEGFA promoter. [ 80 ] In this study, we present the first evidence that, in ECs, SerRS can be O‐GlcNAcylated at Ser101, accordingly leading to the suppression of its importin α 5‐mediated nuclear translocation and its increased degradation by ubiquitination, which reduces its competitive binding to the VEGFA proximal promoter with other GC‐TFs and thus facilitates tumor angiogenesis.…”

“…[ 42 ] In addition, the anti‐angiogenetic role of SerRS is inactivated through phosphorylation by ataxia telangiectasia mutated (ATM) and ATM and RAD3‐related (ATR) under hypoxia and starvation. [ 43 ] Therefore, we deduce that HBP‐related metabolic rewiring plausibly mediates BCa neovascularization by regulating SerRS in ECs.…”

Long-chain non-coding RNA MALAT1 upregulates the MMP-2 signaling pathway by inhibiting miR-106a-5p in murine oxygen- induced retinopathy

“…Therefore, new therapeutic targets must be identi ed. The current research hotspot is gene therapy mediated by shRNA, which has been shown to be effective in reducing the number of treatments and sustaining the effect [31][32][33][34][35] . Combined with our ndings, the inhibition of MALAT1/miR-106a-5p/MMP-2 can effectively antagonize RNV formation in ROP.…”