VIRMA-mediated m⁶A modification regulates forebrain formation through modulating ribosome biogenesis.

Abstract

<i>N</i>⁶-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, 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 m⁶A in adapting protein synthesis machinery during brain development.