VIRMA-mediated m6A modification is essential for active ribosome biogenesis

Abstract N6-methyladenosine (m6A) modification plays crucial roles in tissue development and homeostasis. However, the mechanisms underlying cellular adaptation of m6A modification and their impact on protein synthesis machinery remain unclear. VIRMA, the largest and evolutionarily conserved core of the m6A methyltransferase complex, is highly expressed in the embryonic brain and various cancers. Here, we demonstrate that VIRMA-mediated m6A modification is essential for active ribosome biogenesis. VIRMA depletion destabilizes the entire writer complex and reduces m6A levels, leading to decreased proliferation and increased apoptosis of neural progenitor/stem cells (NPCs), ultimately causing severe forebrain developmental defects. Mechanistically, VIRMA depletion impairs ribosome biogenesis by inhibiting mRNA decay, triggering a P53-dependent ribosomal stress response and compromising global protein synthesis. Importantly, these findings extend to human cancer cells, suggesting the conservation of this mechanism. Overall, our study reveals the critical role of m6A in adapting protein synthesis machinery during brain development and in cancer.