MAF1 is a Chronic Repressor of RNA Polymerase III Transcription in the Mouse

Bonhoure, Nicolas; Praz, Viviane; Moir, Robyn D.; Willemin, Gilles; Mange, François; Moret, Catherine; Willis, Ian M.; Hernandez, Nouria

doi:10.1101/775353

Cited by 6 publications

(20 citation statements)

References 54 publications

(75 reference statements)

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“…Whole body knockout of Maf1 in mice results in a striking lean body composition and resistance to diet-induced obesity 11 . These phenotypes are due in part to metabolic inefficiencies that are thought to be driven by a futile cycle of tRNA synthesis and degradation that wastes cellular energy and reprograms central metabolic pathways [11][12][13] . The ability of Maf1 to affect body composition and metabolism under this model is supported by its function in mammals as chronic Pol III repressor whose activity can be enhanced by limiting nutrients and stressors 13,14 .…”

Section: Introductionmentioning

confidence: 99%

“…These phenotypes are due in part to metabolic inefficiencies that are thought to be driven by a futile cycle of tRNA synthesis and degradation that wastes cellular energy and reprograms central metabolic pathways [11][12][13] . The ability of Maf1 to affect body composition and metabolism under this model is supported by its function in mammals as chronic Pol III repressor whose activity can be enhanced by limiting nutrients and stressors 13,14 . Maf1 expression also promotes the differentiation of mouse embryonic stem cells into mesoderm and the differentiation of NIH3T3-L1 cells into adipocytes 15 .…”

Section: Introductionmentioning

confidence: 99%

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Structural basis of RNA polymerase III transcription repression by Maf1

Vorländer¹,

Baudin²,

Moir³

et al. 2019

Preprint

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Maf1 is a highly conserved central regulator of transcription by RNA polymerase III (Pol III), and Maf1 activity influences a wide range of phenotypes from metabolic efficiency to lifespan. Here, we present a 3.3 Å cryo-EM structure of yeast Maf1 bound to Pol III, which establishes how Maf1 achieves transcription repression. In the Maf1-bound state, Pol III elements that are involved in transcription initiation are sequestered, and the active site is sealed off due to ordering of the mobile C34 winged helix 2 domain. Specifically, the Maf1 binding site overlaps with the binding site of the Pol III transcription factor TFIIIB and DNA in the pre-initiation complex, rationalizing that binding of Maf1 and TFIIIB to Pol III are mutually exclusive. We validate our structure using variants of Maf1 with impaired transcription-inhibition activity. These results reveal the exact mechanism of Pol III inhibition by Maf1, and rationalize previous biochemical data.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structural basis of RNA polymerase III transcription repression by Maf1

Vorländer¹,

Baudin²,

Moir³

et al. 2019

Preprint

Self Cite

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“…When active, Maf1 directly targets the Brf1 subunit of TFIIIB and RNAPIII to inhibit transcription. In addition, in proliferating and differentiated mammalian cells, Maf1 chronically represses RNAPIII transcription to balance RNA synthesis with cellular demand (43,44). Thus, if the mechanism underlying MHV68 induction of pre-tRNAs involved antagonizing Even though the relative increases in pre-tRNA-Tyr levels were dramatically larger in MHV68-infected cells compared to cells lacking Maf1 ( Figure 3B,D), we were struck by the observation that the increase in RNAPIII occupancy in these two scenarios was comparable ( Figure 3A,C).…”

Section: Mhv68 Induces Differential Expression Of Pre-trna Fragmentsmentioning

confidence: 99%

Alteration of the premature tRNA landscape by gammaherpesvirus infection

Tucker

Schaller

Willis

et al. 2019

Preprint

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12Transfer RNAs (tRNAs) are transcribed by RNA polymerase III (RNAPIII) and play a 13 central role in decoding our genome. Many DNA tumor viruses enhance the activity of RNAPIII, 14 yet whether infection alters tRNA expression is largely unknown. Here, we present the first 15 genome wide analysis of how viral infection alters the tRNAome. Using a tRNA-specific 16 sequencing method (DM-tRNA-seq), we find that the murine gammaherpesvirus MHV68 17 induces global changes in pre-tRNA expression, indicating that differential tRNA gene induction 18 is a characteristic of DNA virus infection. Elevated pre-tRNA expression corresponds to 19 increased RNAPIII occupancy, but post-transcriptional mechanisms also contribute. Pre-tRNA 20 accumulation, but not RNAPIII recruitment, requires the virally encoded mRNA endonuclease 21 muSOX, suggesting interplay between the different facets of virus-induced gene regulation. 22Collectively, these findings reveal pervasive changes to tRNA expression during DNA virus 23 infection and highlight the potential of using viruses to explore tRNA biology. 24 25 Impact 26 The first genome-wide analysis of virus-induced tRNA expression changes reveals that 27 tRNA transcription and processing are perturbed by the gammaherpesvirus MHV68. 28 29 30The elegant design of the tRNA decoder, an adaptor molecule which converts genetic 31 information into protein, was proposed over 60 years ago (1). Although tRNAs were the first 32 non-coding RNA described, our understanding of tRNA biology, especially their functions 33 outside of protein translation and what dictates their expression, remains limited. This is partly 34 due to the difficulties in applying RNA sequencing and analysis platforms to tRNAs, but recent 35 methodological advances have resulted in a surge of new studies that help to resolve these 36 complexities (2-4). Non-canonical functions of tRNA transcripts have been described, namely 37 the discovery that both premature and mature tRNAs undergo fragmentation into shorter RNAs 38 with numerous regulatory functions in response to stress, cancer, and viral infection (reviewed 39 in (5, 6)). Given the evidence that the ~400 predicted tRNA genes in mammalian genomes are 40 differentially expressed across cell lines (7-9) and that viral infection can lead to post-41 transcriptional modulation of tRNAs (10, 11), defining the tRNAome under varying conditions will 42 be central to our understanding of tRNA function, canonical and otherwise. 43RNA polymerase III (RNAPIII) transcribes tRNA genes and exhibits enhanced activity 44 during infection with DNA viruses (12-17), many of which encode their own RNAPIII genes. 45Though RNAPIII activation stimulates expression of viral RNAPIII genes, concomitant 46 accumulation of host RNAPIII transcripts can trigger antiviral immune responses. For example, 47 the induction or misprocessing of RNAPIII-generated host 5S RNA pseudogene and vault RNA 48 transcripts during Herpes Simplex Virus-1 (HSV-1) and Kaposi's sarcoma-associated 49 herpesvirus (KSHV) infection...

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“…In mammalian cells, MAF1 represses Pol III transcription not only under stress conditions such as rapamycin treatment but also under optimal growth conditions, albeit to a lesser extent (Reina et al, 2006;Orioli et al, 2016). Indeed, the livers of Maf1 −/− mice display higher Pol III occupancy of Pol III genes in both fasted and refed states and the levels of short-lived precursor tRNAs, which reflect transcription activity, are elevated in multiple tissues (Bonhoure et al, 2020). Mammalian MAF1 thus keeps Pol III transcription in check under many different conditions.…”

Section: Introductionmentioning

confidence: 99%

Contrasting effects of whole-body and hepatocyte-specific deletion of the RNA polymerase III repressor Maf1 in the mouse

Willemin,

Mange,

Praz

et al. 2023

Front. Mol. Biosci.

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MAF1 is a nutrient-sensitive, TORC1-regulated repressor of RNA polymerase III (Pol III). MAF1 downregulation leads to increased lipogenesis in Drosophila melanogaster, Caenorhabditis elegans, and mice. However, Maf1−/− mice are lean as increased lipogenesis is counterbalanced by futile pre-tRNA synthesis and degradation, resulting in increased energy expenditure. We compared Chow-fed Maf1−/− mice with Chow- or High Fat (HF)-fed Maf1hep−/− mice that lack MAF1 specifically in hepatocytes. Unlike Maf1−/− mice, Maf1hep−/− mice become heavier and fattier than control mice with old age and much earlier under a HF diet. Liver ChIPseq, RNAseq and proteomics analyses indicate increased Pol III occupancy at Pol III genes, very few differences in mRNA accumulation, and protein accumulation changes consistent with increased lipogenesis. Futile pre-tRNA synthesis and degradation in the liver, as likely occurs in Maf1hep−/− mice, thus seems insufficient to counteract increased lipogenesis. Indeed, RNAseq and metabolite profiling indicate that liver phenotypes of Maf1−/− mice are strongly influenced by systemic inter-organ communication. Among common changes in the three phenotypically distinct cohorts, Angiogenin downregulation is likely linked to increased Pol III occupancy of tRNA genes in the Angiogenin promoter.

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MAF1 is a Chronic Repressor of RNA Polymerase III Transcription in the Mouse

Cited by 6 publications

References 54 publications

Structural basis of RNA polymerase III transcription repression by Maf1

Structural basis of RNA polymerase III transcription repression by Maf1

Alteration of the premature tRNA landscape by gammaherpesvirus infection

Contrasting effects of whole-body and hepatocyte-specific deletion of the RNA polymerase III repressor Maf1 in the mouse

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