Maf1 limits RNA polymerase III-directed transcription to preserve genomic integrity and extend lifespan

Area of Science:

• Cellular and Molecular Biology
• Genetics and Genomics
• Aging Research

Background:

• The mechanistic target of rapamycin (mTOR) pathway is a critical regulator of longevity.
• Inhibition of mTOR signaling extends lifespan across diverse organisms.
• Downstream targets of mTOR involved in lifespan regulation remain largely unidentified.

Purpose of the Study:

• To identify downstream effectors of the mTOR pathway that regulate lifespan.
• To investigate the role of Maf1 in mTOR-mediated lifespan extension.
• To elucidate the mechanisms by which Maf1 influences longevity and genomic integrity.

Main Methods:

• Utilized fission yeast as a model organism.
• Investigated the regulation of Maf1 by mTOR-mediated phosphorylation.
• Assessed the impact of Maf1 on lifespan under conditions of calorie restriction and mTOR inhibition.
• Examined the role of Maf1 in preventing DNA damage at transfer RNA (tRNA) genes.

Main Results:

• Identified Maf1 as a critical lifespan regulator downstream of mTOR in fission yeast.
• Demonstrated that Maf1 is essential for lifespan extension induced by calorie restriction or mTOR inhibition.
• Showed that Maf1 functions as a master negative regulator of RNA polymerase III transcription.
• Provided evidence that Maf1 prevents DNA damage at tRNA genes, contributing to lifespan maintenance.

Conclusions:

• The mTOR-Maf1-Pol III axis plays a significant role in promoting genomic integrity.
• Maf1's function in maintaining genomic stability, particularly at tRNA genes, is vital for normal lifespan.
• This axis addresses DNA replication-transcription conflicts, highlighting a novel mechanism for lifespan assurance.