Structural basis for RNA polymerase III transcription repression by Maf1

Vorländer, Matthias K.; Baudin, Florence; Moir, Robyn D.; Wetzel, René; Hagen, Wim J. H.; Willis, Ian M.; Müller, Christoph W.

doi:10.1038/s41594-020-0383-y

Cited by 43 publications

(26 citation statements)

References 29 publications

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“…Finally, functional studies of POLR3A mutations associated with POLR3-HLD have demonstrated transcriptional defects when introduced in both yeast and human cells (Choquet et al, 2019a ; Moir et al, 2020 ). Further research on molecular pathways and other POLR3 interactors will be valuable in determining whether suppression of upstream POLR3 inhibitors, such as MAF1 (Reina et al, 2006 ; Johnson et al, 2007 ; Bonhoure et al, 2020 ; Vorländer et al, 2020 ), are appropriate for future treatments. It is also possible that a small molecule screening approach could identify drugs for the treatment of specific molecular mechanisms, such as upregulation of complex assembly cofactors or signaling molecules for nuclear import of POLR3 (Cloutier and Coulombe, 2010 ; Lesniewska and Boguta, 2017 ; Willis and Moir, 2018 ).…”

Section: Polr3-related Leukodystrophy: Approaching Treatment Optionsmentioning

confidence: 99%

POLR3-Related Leukodystrophy: Exploring Potential Therapeutic Approaches

Perrier

Michell‐Robinson

Bernard

2021

Front. Cell. Neurosci.

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Leukodystrophies are a class of rare inherited central nervous system (CNS) disorders that affect the white matter of the brain, typically leading to progressive neurodegeneration and early death. Hypomyelinating leukodystrophies are characterized by the abnormal formation of the myelin sheath during development. POLR3-related or 4H (hypomyelination, hypodontia, and hypogonadotropic hypogonadism) leukodystrophy is one of the most common types of hypomyelinating leukodystrophy for which no curative treatment or disease-modifying therapy is available. This review aims to describe potential therapies that could be further studied for effectiveness in pre-clinical studies, for an eventual translation to the clinic to treat the neurological manifestations associated with POLR3-related leukodystrophy. Here, we discuss the therapeutic approaches that have shown promise in other leukodystrophies, as well as other genetic diseases, and consider their use in treating POLR3-related leukodystrophy. More specifically, we explore the approaches of using stem cell transplantation, gene replacement therapy, and gene editing as potential treatment options, and discuss their possible benefits and limitations as future therapeutic directions.

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Section: Polr3-related Leukodystrophy: Approaching Treatment Optionsmentioning

confidence: 99%

POLR3-Related Leukodystrophy: Exploring Potential Therapeutic Approaches

Perrier

Michell‐Robinson

Bernard

2021

Front. Cell. Neurosci.

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“…Lipid accumulation of C. elegans in response to UV light exposure Although Maf1 function, and its role in the DNA damage response (DDR), has been widely researched in cultured yeast and mammalian cell models (Ghavidel and Schultz, 2001;Pluta et al, 2001;Upadhya et al, 2002;Reina et al, 2006;Johnson et al, 2007;Goodfellow et al, 2008;Vannini et al, 2010;Palian et al, 2014;Lee et al, 2015;Li et al, 2016;Shetty et al, 2020;Vorlander et al, 2020), fewer studies have been carried out in whole animals (Marshall et al, 2012;Khanna et al, 2014;Bonhoure et al, 2015;Pradhan et al, 2017). To test whether C. elegans mafr-1 mediates organismal responses to UV light exposure, we analyzed animals carrying the CRISPR/Cas9-mediated deletion of the entire mafr-1 locus, hereafter referred to as mafr-1 knockout (KO), as compared with wild-type (WT) control animals.…”

Section: Resultsmentioning

confidence: 99%

“…Dysregulation of these functions is associated with the molecular under-pinnings of various disease states, which can lead to obesity, metabolic disease, or cancer (Willis and Moir, 2007;Khanna et al, 2015;Johnson and Stiles, 2016). Maf1 physically associates with TFIIIB and RNA pol III and prevents its transcription of rRNA, noncoding RNA (ncRNA), and (primarily) tRNA (Vannini et al, 2010;Vorlander et al, 2020). Study on glioblastoma cells reveals that Maf1 also regulates a subset of RNA pol I and pol II gene targets (Johnson et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Maf1 regulates intracellular lipid homeostasis in response to DDR activation

Hammerquist

Escorcia

Curran

2021

MBoC

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Surveillance of DNA damage and maintenance of lipid metabolism are critical factors for general cellular homeostasis. We discovered that in response to DNA damage-inducing UV light exposure, intact C. elegans accumulate intracellular lipids in a dose dependent manner. The increase in intracellular lipids in response to exposure to UV light utilizes mafr-1, a negative regulator of RNA polymerase III and the apical kinases atm-1 and atl-1 of the DNA damage response (DDR) pathway. In the absence of exposure to UV light, the genetic ablation of mafr-1 results in the activation of the DDR including increased intracellular lipid accumulation, phosphorylation of ATM/ATR targets proteins, and expression of the Bcl-2 homology region genes, egl-1 and ced-13. Taken together, our study reveals a places mafr-1 as a component the DDR pathway response to regulating lipid homeostasis following exposure to UV genotoxic stress.

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“…The latter is negatively regulated via phosphorylation by the mTOR pathway and tailors 5S rRNA and tRNA production in response to various environmental cues [ 60 ]. Recent data have shown that the Maf1 binding site on Pol III overlaps with that of TFIIIB in the preinitiation complex [ 61 ]. Deletion of maf1 in the budding yeast Saccharomyces cerevisiae but not its homologue mafr-1 in C. elegans prevents dietary restriction or caloric restriction to extend lifespan.…”

Section: Lifespan Effects Of Mtor Through Regulation Of Gene Transmentioning

confidence: 99%

The Target of Rapamycin Signalling Pathway in Ageing and Lifespan Regulation

Bjedov

Rallis

2020

Genes

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Ageing is a complex trait controlled by genes and the environment. The highly conserved mechanistic target of rapamycin signalling pathway (mTOR) is a major regulator of lifespan in all eukaryotes and is thought to be mediating some of the effects of dietary restriction. mTOR is a rheostat of energy sensing diverse inputs such as amino acids, oxygen, hormones, and stress and regulates lifespan by tuning cellular functions such as gene expression, ribosome biogenesis, proteostasis, and mitochondrial metabolism. Deregulation of the mTOR signalling pathway is implicated in multiple age-related diseases such as cancer, neurodegeneration, and auto-immunity. In this review, we briefly summarise some of the workings of mTOR in lifespan and ageing through the processes of transcription, translation, autophagy, and metabolism. A good understanding of the pathway’s outputs and connectivity is paramount towards our ability for genetic and pharmacological interventions for healthy ageing and amelioration of age-related disease.

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Structural basis for RNA polymerase III transcription repression by Maf1

Cited by 43 publications

References 29 publications

POLR3-Related Leukodystrophy: Exploring Potential Therapeutic Approaches

POLR3-Related Leukodystrophy: Exploring Potential Therapeutic Approaches

Maf1 regulates intracellular lipid homeostasis in response to DDR activation

The Target of Rapamycin Signalling Pathway in Ageing and Lifespan Regulation

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