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

## TL;DR

This study shows that the interaction between SMN and METTL14, which depends on arginine methylation, is crucial for maintaining RNA m6A levels and DNA repair, with implications for diseases like spinal muscular atrophy.

## Contribution

The study identifies a novel arginine methylation-dependent interaction between SMN and METTL14 that regulates m6A homeostasis and DNA repair.

## Key findings

- SMN binds METTL14 via its Tudor domain in an arginine methylation-dependent manner.
- SMA-related SMN mutations reduce m6A levels and DNA repair gene expression in patient fibroblasts.
- Mettl14 methylation-deficient mice show embryonic lethality and abnormal hematopoiesis.

## Abstract

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 (Mettl14RK). 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.

SMN interacts with METTL14 in an arginine methylation-dependent manner. This interaction is critical for cellular m6A homeostasis, genome stability, and normal hematopoiesis.

SMN interacts with METTL14 in an arginine methylation-dependent manner.Proper SMN expression is critical for cellular m6A homeostasis.SMN loss-of-function mutation reduces DNA repair gene expression.METTL14 arginine methylation deficiency impairs normal hematopoiesis.

SMN interacts with METTL14 in an arginine methylation-dependent manner.

Proper SMN expression is critical for cellular m6A homeostasis.

SMN loss-of-function mutation reduces DNA repair gene expression.

METTL14 arginine methylation deficiency impairs normal hematopoiesis.

SMN interacts with METTL14 in an arginine methylation-dependent manner. This interaction is critical for cellular m6A homeostasis, genome stability, and normal hematopoiesis.