VIRMA-mediated mA modification regulates forebrain formation through modulating ribosome biogenesis.

-Methyladenosine (mA) modification plays crucial roles in tissue development and homeostasis. However, the mechanisms underlying cellular adaptation of mA modification and their impact on protein synthesis machinery remain unclear. VIRMA, the largest and evolutionarily conserved core of the mA methyltransferase complex, is highly expressed in the embryonic brain and various cancers. Here, we demonstrate that VIRMA-mediated mA modification is essential for active ribosome biogenesis. VIRMA depletion destabilizes the entire writer complex and reduces mA levels, leading to decreased proliferation and increased apoptosis of neural progenitor/stem cells, ultimately causing severe forebrain developmental defects. Mechanistically, VIRMA depletion impairs ribosome biogenesis by inhibiting mRNA decay, triggering a p53-dependent stress response and compromising global protein synthesis. These findings extend to some cancer cells, suggesting a potential conservation of this mechanism. Overall, our study reveals the critical role of mA in adapting protein synthesis machinery during brain development.