Deficiency of N1-Adenine Methyltransferase Aggravates RNA and Protein Aggregation

Area of Science:

• Molecular Biology
• Epigenetics
• RNA Biology

Background:

• RNA modifications regulate gene expression and stability.
• N1-methyladenine (m¹A) is a reversible RNA mark involved in stress response.
• The role of m¹A in chronic proteotoxic stress, like amyloid aggregation, is unclear.

Purpose of the Study:

• Investigate the function of m¹A during intracellular amyloid aggregation.
• Determine the impact of reduced N1-adenine methylation on proteostasis.
• Elucidate the protective mechanisms conferred by m¹A.

Main Methods:

• Studied human cells undergoing amyloidogenesis with altered m¹A levels.
• Manipulated TRMT61A (methyltransferase) and ALKBH3 (demethylase) expression.
• Analyzed reporter mRNA-protein expression and proteomic profiles of amyloid aggregates.

Main Results:

• Suppression of TRMT61A or ALKBH3 overexpression enhanced amyloid aggregation.
• Deficiency in N1-adenine methylation impaired reporter mRNA-protein expression.
• Amyloid aggregates in methylation-deficient cells showed increased co-aggregation of RNA-binding proteins and elevated mRNA levels.

Conclusions:

• m¹A plays a crucial role in protecting cells against chronic proteotoxic stress.
• m¹A safeguards transcript functionality and prevents RNA entanglement within aggregates.
• m¹A limits the RNA-mediated propagation of protein co-aggregation.