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

Area of Science:

• Molecular Biology
• Epigenetics
• Developmental Biology

Background:

• N6-methyladenosine (m⁶A) homeostasis is crucial for development, with its dysregulation implicated in diseases like cancer and neurological disorders.
• The precise mechanisms governing m⁶A regulation are not fully understood.
• The survival of motoneuron (SMN) protein is vital for motor neuron function.

Purpose of the Study:

• To identify novel regulators of m⁶A homeostasis.
• To investigate the role of SMN protein in m⁶A modification.
• To explore the link between m⁶A dysregulation and spinal muscular atrophy (SMA).

Main Methods:

• Protein-protein interaction studies to identify SMN as a METTL14 binding partner.
• Analysis of m⁶A levels in patient-derived fibroblasts with SMA-associated mutations.
• Assessment of DNA repair gene expression and sensitivity to DNA-damaging agents.
• Generation and analysis of a methylation-deficient Mettl14 mouse model.

Main Results:

• SMN protein directly binds to METTL14 via its Tudor domain in an arginine methylation-dependent manner.
• SMA-associated mutations in the SMN Tudor domain disrupt METTL14 interaction and reduce global m⁶A levels.
• SMN deficiency and SMA mutations impair m⁶A deposition on DNA repair gene mRNAs, leading to hypersensitivity to DNA damage in SMA fibroblasts.
• The Mettl14 methylation-deficient mouse model exhibits partial embryonic lethality and hematopoiesis defects, indicating a role in early development.

Conclusions:

• SMN is a novel regulator of m⁶A homeostasis, interacting with the METTL14 complex.
• m⁶A dysregulation, mediated by SMN-METTL14 interaction, contributes to SMA pathology and DNA repair defects.
• Methylated METTL14 plays a significant role in embryonic development and hematopoiesis.