Arginine methylation-dependent METTL14-SMN interaction regulates RNA mA homeostasis.

Abstract

N6-methyladenosine (mA) homeostasis is essential for development, and its dysregulation is linked to cancers and neurological disorders. However, the mechanisms regulating mA remain unclear. Here, we identify the survival of motoneuron (SMN) protein as a novel interaction partner of METTL14, a key component of the mA 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 mA levels in patient-derived fibroblasts, linking mA dysregulation to SMA pathology. Both SMN knockdown and SMA mutations impair mA 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). 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.