DNA methyltransferase 1 modulates mitochondrial function through bridging m⁵C RNA methylation.

Area of Science:

• Molecular Biology
• Neuroscience
• Epigenetics

Background:

• DNA methyltransferase 1 (DNMT1) is crucial for maintaining DNA methylation patterns.
• Mutations in the DNMT1 replication focus targeting sequence (RFTS) domain are linked to neurodegenerative disorders like autosomal dominant cerebellar ataxia-deafness and narcolepsy (ADCA-DN).

Purpose of the Study:

• To investigate the non-canonical functions of DNMT1 beyond DNA methylation.
• To elucidate the role of DNMT1 in RNA methylation and its contribution to neurodegeneration.

Main Methods:

• Investigated DNMT1's interaction with mRNA transcripts in vitro and in vivo.
• Utilized mouse models with mutated DNMT1 RFTS domains.
• Assessed RNA methylation levels (m5C) and RNA stability.
• Analyzed gene expression of metabolic genes and mitochondrial function markers.

Main Results:

• DNMT1 directly binds to mRNA and facilitates 5-methylcytosine (m5C) RNA methylation by recruiting NSUN2.
• Mutations in the DNMT1 RFTS domain lead to aberrant DNMT1-RNA interactions and increased m5C RNA methylation.
• Elevated m5C RNA methylation enhances the stability of metabolic gene transcripts.
• This leads to oxidative stress, mitochondrial dysfunction, and neurological symptoms in mice.

Conclusions:

• DNMT1 plays a dual role in regulating both DNA and RNA methylation.
• Aberrant RNA methylation by mutated DNMT1 contributes to neurodegeneration through mitochondrial dysfunction.
• This study reveals a novel pathogenic mechanism for DNMT1 mutation-induced neurodegenerative diseases.