Arginine methylation-dependent METTL14-SMN interaction regulates RNA m⁶A homeostasis

N6-methyladenosine (m⁶A) homeostasis is essential for development, and its dysregulation is linked to cancers and neurological disorders. However, the mechanisms regulating m⁶A remain unclear. Here, we identify the survival of motoneuron (SMN) protein as a novel interaction partner of METTL14, a key component of the m⁶A methyltransferase complex. SMN binds METTL14 via its Tudor domain in an arginine methylation-dependent manner. Mutations in the SMN Tudor domain identified in spinal muscular atrophy (SMA) disrupt its interaction with METTL14 and reduce m⁶A levels in patient-derived fibroblasts, linking m⁶A dysregulation to SMA pathology. Both SMN knockdown and SMA mutations impair m⁶A deposition on the mRNAs of DNA repair genes, mirroring the effects of METTL14 hypomethylation. Consequently, SMA patient fibroblasts are hypersensitive to DNA-damaging agents due to reduced levels of DNA repair gene expression. To explore the function of METTL14 arginine methylation in vivo, we generated a Mettl14 methylation-deficient mouse model (Mettl14^RK). Although this model does not show SMA-like phenotypes, the mutants are partially embryonic lethal and show abnormal hematopoiesis, underscoring a role for methylated METTL14 in early development.