tRNA synthetase counteracts c-Myc to develop functional vasculature

Area of Science:

• Molecular Biology
• Developmental Biology
• Biochemistry

Background:

• Seryl-tRNA synthetase (SerRS) has a non-canonical role in vascular development, independent of protein synthesis.
• This function is linked to a unique nucleus-directing domain acquired during vertebrate evolution.
• Previous work indicated SerRS controls VEGFA expression to prevent vascular overgrowth.

Purpose of the Study:

• To elucidate the mechanism by which SerRS regulates VEGFA expression and vascular development.
• To investigate the interaction between SerRS and the transcription factor c-Myc.
• To identify the role of SIRT2 histone deacetylase in this process.

Main Methods:

• In vitro assays
• Cell-based experiments
• Animal models
• Analysis of protein-DNA interactions
• Histone acetylation assays

Main Results:

• SerRS directly competes with c-Myc for binding to the VEGFA promoter.
• Nuclear-localized SerRS blocks c-Myc-mediated VEGFA transcription.
• SerRS recruits SIRT2 to deacetylate histones, further suppressing VEGFA expression.
• SIRT2 exhibits anti-angiogenic activity.

Conclusions:

• Vertebrate SerRS and c-Myc act as a 'Yin-Yang' pair to regulate VEGFA, ensuring proper vascular development.
• SerRS utilizes a dual mechanism involving promoter competition and epigenetic modification to control vascular expansion.
• SIRT2 plays a critical role in SerRS-mediated vascular regulation.