Maf1‐dependent transcriptional regulation of tRNAs prevents genomic instability and is associated with extended lifespan

Autor: Eishi Noguchi, Joshua Chang Mell, Sydney Wilson, Esteban Martínez, Christian Sell, Mihir Shetty, Kazuhiro Shiozaki, Chiaki Noguchi
Rok vydání: 2019
Předmět:
0301 basic medicine
Genome instability
RNA polymerase III
Aging
Medical and Health Sciences
0302 clinical medicine
RNA
Transfer
Gene Expression Regulation
Fungal
Phosphoprotein Phosphatases
Protein biosynthesis
Transcriptional regulation
Protein Phosphatase 2
Phosphorylation
Biological Sciences
Cell biology
Fungal
Original Article
transcription
Maf1
lifespan
Chromatin Immunoprecipitation
DNA damage
DNA repair
1.1 Normal biological development and functioning
Mechanistic Target of Rapamycin Complex 1
Biology
Genomic Instability
03 medical and health sciences
Underpinning research
Schizosaccharomyces
DNA Repair Protein
Genetics
tRNA
PI3K/AKT/mTOR pathway
aging
Original Articles
Cell Biology
Rad52 DNA Repair and Recombination Protein
Repressor Proteins
Transfer
Glucose
030104 developmental biology
Gene Expression Regulation
Protein Biosynthesis
RNA
Schizosaccharomyces pombe Proteins
Generic health relevance
030217 neurology & neurosurgery
Developmental Biology
Zdroj: Aging cell, vol 19, iss 2
Aging Cell
ISSN: 1474-9726
1474-9718
Popis: Maf1 is the master repressor of RNA polymerase III responsible for transcription of tRNAs and 5S rRNAs. Maf1 is negatively regulated via phosphorylation by the mTOR pathway, which governs protein synthesis, growth control, and lifespan regulation in response to nutrient availability. Inhibiting the mTOR pathway extends lifespan in various organisms. However, the downstream effectors for the regulation of cell homeostasis that are critical to lifespan extension remain elusive. Here we show that fission yeast Maf1 is required for lifespan extension. Maf1’s function in tRNA repression is inhibited by mTOR‐dependent phosphorylation, whereas Maf1 is activated via dephosphorylation by protein phosphatase complexes, PP4 and PP2A. Mutational analysis reveals that Maf1 phosphorylation status influences lifespan, which is correlated with elevated tRNA and protein synthesis levels in maf1∆ cells. However, mTOR downregulation, which negates protein synthesis, fails to rescue the short lifespan of maf1∆ cells, suggesting that elevated protein synthesis is not a cause of lifespan shortening in maf1∆ cells. Interestingly, maf1∆ cells accumulate DNA damage represented by formation of Rad52 DNA damage foci and Rad52 recruitment at tRNA genes. Loss of the Rad52 DNA repair protein further exacerbates the shortened lifespan of maf1∆ cells. Strikingly, PP4 deletion alleviates DNA damage and rescues the short lifespan of maf1∆ cells even though tRNA synthesis is increased in this condition, suggesting that elevated DNA damage is the major cause of lifespan shortening in maf1∆ cells. We propose that Maf1‐dependent inhibition of tRNA synthesis controls fission yeast lifespan by preventing genomic instability that arises at tRNA genes.
In response to nutrient availability, mTOR inactivates Maf1 via phosphorylation. This results in hyperactivation of Pol III‐mediated transcription, leading to DNA damage due to collisions between the replication and transcription machineries. Such DNA damage may shorten lifespan. mTOR‐mediated activation of cellular processes and increased energy expenditure also negatively affect lifespan.
Databáze: OpenAIRE
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