Ribosomes are tiny molecular machines inside all living cells that build proteins, and ribosome biogenesis is the complex, multi-step process by which they are made.
During brain development, neural stem cell proliferation relies on active ribosome biogenesis to meet high protein demand. This process involves the concerted action of numerous ribosomal RNA processing factors and assembly proteins. Studies have shown that precise regulation of ribosome biogenesis is essential for normal brain development and tumor prevention.
N6-Methyladenosine (m6A) is a widespread post-transcriptional modification in eukaryotes that plays crucial roles in tissue development and homeostasis. However, the mechanisms underlying cellular adaptation to m6A modification and their impact on protein synthesis machinery have not been well understood.
In a study published in Science Advances, a collaborative team led by Prof. ZHOU Tao from the Shenzhen Institute of Advanced Technology of the Chinese Academy of Sciences and Prof. SHEN Bin from Nanjing Medical University has revealed that VIRMA, a protein highly expressed in the embryonic brain and various cancers, regulates brain development by modulating ribosome biogenesis.
VIRMA is an evolutionarily conserved core scaffold protein within the m6A methyltransferase complex and is its largest component. Using conditional knockout mice and neural stem cell models, the researchers explored the role of VIRMA in brain development through comprehensive biochemical analyses and multi-omics sequencing.
Through RNA and m6A sequencing and proteomics analysis, the researchers revealed that VIRMA depletion led to a significant reduction in m6A levels on mRNA, directly impacting the expression of genes involved in ribosome biogenesis. Specifically, VIRMA depletion prolonged the half-lives of mRNA involved in ribosome biogenesis, thereby impairing key steps in this process. Consequently, it triggered a p53-dependent stress response, disrupted global protein translation, and impaired cell growth and proliferation. These disruptions ultimately resulted in severe developmental defects.
To evaluate the broader relevance of these findings, the researchers performed preliminary analyses using human breast cancer (MCF7) and cervical cancer (HeLa) cell models. They observed comparable defects in ribosome biogenesis in VIRMA-depleted cancer cells, suggesting a potential conservation of this regulatory mechanism across cell types.
This study expands the understanding of the complex regulatory networks that govern protein synthesis and underscores the critical role of mRNA modifications in fine-tuning essential cellular processes.
