Emerging Roles for Maf1 beyond the Regulation of RNA Polymerase III Activity

Khanna, Akshat; Pradhan, Ajay; Curran, Sean P.

doi:10.1016/j.jmb.2015.06.022

Cited by 24 publications

(22 citation statements)

References 51 publications

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“…Maf1 inhibits tRNA transcription in S. cerevisiae , Drosophila , C. elegans , mice, and human cells under various stress conditions including calorie restriction (Khanna, Pradhan, & Curran, ). A recent report also showed that rapamycin decreases tRNA transcription in a Maf1‐dependent manner in S. pombe (Arimbasseri et al, ).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2019

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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.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2019

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“…The underlying mechanism for MAF1 recruitment, in any organism, to chromatin is unknown, even more so for non-RNA pol III loci. Several models agree that MAF1 can interact with either RNA pol III itself or transcription factors to prevent transcription [5,6,10,11,16,17,24,27,28]. The expressions of pod-2/ACC1 and fasn-1/FASN are regulated by RNA pol II and SREBPs in C. elegans and mammals.…”

Section: Discussionmentioning

confidence: 99%

The C-Box Region of MAF1 Regulates Transcriptional Activity and Protein Stability

Pradhan

Hammerquist

Khanna

et al. 2017

Journal of Molecular Biology

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MAF1 is a conserved negative regulator of RNA polymerase (pol) III and intracellular lipid homeostasis across species. Here, we show that the MAF1 C-box region negatively regulates its activity. Mutations in Caenorhabditis elegans mafr-1 that truncate the C-box retain the ability to inhibit the transcription of RNA pol III targets, reduce lipid biogenesis, and lower reproductive output. In human cells, C-box deletion of MAF1 leads to increased MAF1 nuclear localization and enhanced repression of ACC1 and FASN, but with impaired repression of RNA pol III targets. Surprisingly, C-box mutations render MAF1 insensitive to rapamycin, further defining a regulatory role for this region. Two MAF1 species, MAF1L and MAF1S, are regulated by the C-box YSY motif, which, when mutated, alters species stoichiometry and proteasome-dependent turnover of nuclear MAF1. Our results reveal a role for the C-box region as a critical determinant of MAF1 stability, activity, and response to cellular stress.

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“…In eukaryotes, RNA polymerase III transcribes tRNA genes, and this activity is regulated by different signaling pathways in response to growth factors, nutrient levels, mitogens, or stress (Dang 2012;Grewal 2015;Khanna et al 2015). Through protein kinase mTORC1, Maf 1 is a major repressor (Kantidakis et al 2010;Grewal 2015).…”

Section: The State Of the Trna Population In The Cellmentioning

confidence: 99%

Protein folding and tRNA biology

2017

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Polypeptides can fold into tertiary structures while they are synthesized by the ribosome. In addition to the amino acid sequence, protein folding is determined by several factors within the cell. Among others, the folding pathway of a nascent polypeptide can be affected by transient interactions with other proteins, ligands, or the ribosome, as well as by the translocation through membrane pores. Particularly, the translation machinery and the population of tRNA under different physiological or adaptive responses can dramatically affect protein folding. This review summarizes the scientific evidence describing the role of translation kinetics and tRNA populations on protein folding and addresses current efforts to better understand tRNA biology. It is organized into three main parts, which are focused on: (i) protein folding in the cellular context; (ii) tRNA biology and the complexity of the tRNA population; and (iii) available methods and technical challenges in the characterization of tRNA pools. In this manner, this work illustrates the ways by which functional properties of proteins may be modulated by cellular tRNA populations.

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Emerging Roles for Maf1 beyond the Regulation of RNA Polymerase III Activity

Cited by 24 publications

References 51 publications

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

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

The C-Box Region of MAF1 Regulates Transcriptional Activity and Protein Stability

Protein folding and tRNA biology

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