Blocking the Effect of ATM/ATR on Seryl-tRNA Synthetase Can Reduce Tumor Growth

Blocking the Effect of ATM/ATR on Seryl-tRNA Synthetase Can Reduce Tumor Growth

Oxygen is essential for the development and growth of most multicellular organisms. Even cancerous tumors. That's why in the absence of oxygen, tumors can easily grow new blood vessels, creating a new lifeline for survival. In a new study, researchers from Scripps Research and Nankai University in China have pinpointed the molecular mechanisms that make this happen, and provided scientific insights, making it possible to develop drugs that help kill tumors and prevent their spread in the body. The related research results were recently published in the journal PLOS Biology with the title of "Phosphorylation of seryl-tRNA synthetase by ATM/ATR is essential for hypoxia-induced angiogenesis".

Complex molecular mechanisms have been evolved to sense and respond to changes in oxygen levels to maintain cell and tissue homeostasis. Thus, the hypoxia response is protective against ischemic tissue injury. In addition, pathophysiological hypoxia signaling also contributes to the development of diseases, such as cardiovascular disorders and solid tumors. In the past decade, Yang and her team have published several key findings about how cells produce blood vessels, delving into previously unknown roles of genes that regulate this function. Previous studies have involved transcription factors like hypoxia-inducible factor 1 (HIF-1) and c-Myc, which promote vascular development and are closely related to cancer.

Blocking the Effect of ATM/ATR on Seryl-tRNA Synthetase Can Reduce Tumor GrowthFigure 1. Schematic diagram to illustrate the impact of SerRS in hypoxia-induced angiogenesis. (Shi Y, et al. 2020)

Previous studies of Yang's team have identified seryl-tRNA synthetase (SerRS) as a key transcriptional repressor of VEGFA. Here, they revealed the importance of silencing negative regulators in this process by studying SerRS. SerRS is inactivated by posttranslational modification via phosphoinositide-3 kinase (PI3K)-like kinase family members ATM and ATR, which are central kinases in DNA damage responses, important for maintaining the stability of mammalian genome under hypoxia stress.

The study suggests that phosphorylation-mediated loss of DNA binding of SerRS under hypoxia is required for c-Myc to bind to the VEGFA promoter. It is worth noting that SerRS can also compete with HIF-1 for binding to the DNA, indicating that SerRS inhibits both HIF-dependent and HIF-independent activation of VEGFA. Thus, blocking the effect of ATM/ATR on SerRS, for instance, through the expression of a phosphorylation-deficient form of SerRS, can act as a major inhibitor of multiple hypoxia response pathways to effectively inhibit angiogenesis. These results with the endothelial cell tube formation assay and in mice demonstrating potent antiangiogenesis and antitumor effect with SerRSAA expression are supportive of this concept.

SerRS is well known as a member of the aminoacyl-tRNA synthetase family that is responsible for charging serine onto its cognate tRNA to generate substrates for protein biosynthesis in the cytosol. It begins the process of making proteins, which form essential components of blood, skin, bone and other human life. The results of this study suggest that SerRS has evolved additional functions in addition to making proteins.

"It's possible that SerRS not only regulates blood vessel development," Yang says. "This is a convincing finding that opens the door to further investigation into how broad its influence may reach in the human body."

Reference

  1. Shi Y, et al. Phosphorylation of seryl-tRNA synthetase by ATM/ATR is essential for hypoxia-induced angiogenesis. PLoS biology, 2020, 18(12): e3000991.

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