RNA Polymerase III Subunit Mutations in Genetic Diseases

Lata, Elisabeth; Choquet, Karine; Sagliocco, Francis; Brais, Bernard; Bernard, Geneviève; Teichmann, Martin

doi:10.3389/fmolb.2021.696438

Cited by 40 publications

(29 citation statements)

References 266 publications

(409 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is a striking observation considering that this job was normally attributed to CTFs and/or certain 3D genome architectural proteins such as CTCF and cohesin [12,52]. Indeed, TFIIIC was previously suggested to contain functional similarities to both general transcription factors and transcriptional activators [53]. Our data also provide evidence that looping-forming TFIIIC-bound regions are devoid of CTCF sites and that TFIIIC sites shared across cell lines have higher level of occupancy for CTCF than at cell type-specific TFIIIC-bound regions.…”

Section: Discussionmentioning

confidence: 93%

An RNA Polymerase III General Transcription Factor Engages in Cell Type-Specific Chromatin Looping

Cucalon

Vona

Morselli

et al. 2022

IJMS

Self Cite

View full text Add to dashboard Cite

Transcription factors (TFs) bind DNA in a sequence-specific manner and are generally cell type-specific factors and/or developmental master regulators. In contrast, general TFs (GTFs) are part of very large protein complexes and serve for RNA polymerases’ recruitment to promoter sequences, generally in a cell type-independent manner. Whereas, several TFs have been proven to serve as anchors for the 3D genome organization, the role of GTFs in genome architecture have not been carefully explored. Here, we used ChIP-seq and Hi-C data to depict the role of TFIIIC, one of the RNA polymerase III GTFs, in 3D genome organization. We find that TFIIIC genome occupancy mainly occurs at specific regions, which largely correspond to Alu elements; other characteristic classes of repetitive elements (REs) such as MIR, FLAM-C and ALR/alpha are also found depending on the cell’s developmental origin. The analysis also shows that TFIIIC-enriched regions are involved in cell type-specific DNA looping, which does not depend on colocalization with the master architectural protein CTCF. This work extends previous knowledge on the role of TFIIIC as a bona fide genome organizer whose action participates in cell type-dependent 3D genome looping via binding to REs.

show abstract

Section: Discussionmentioning

confidence: 93%

An RNA Polymerase III General Transcription Factor Engages in Cell Type-Specific Chromatin Looping

Cucalon

Vona

Morselli

et al. 2022

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…Interestingly, several different syndromes relating to mutations in RNA pol III subunits show very heterogeneous phenotypes. This includes POLR3 -related hypomyelinating leukodystrophies ( Lata et al, 2021 ; Yeganeh and Hernandez, 2020 ; Thomas and Thomas, 2019 ), Wiedemann-Rautenstrauch syndrome, a neonatal progeroid syndrome ( Wu et al, 2021b ; Wambach et al, 2018 ; Paolacci et al, 2017 ; Beauregard-Lacroix et al, 2020 ), and cerebellar hypoplasia with endosteal sclerosis ( Terhal et al, 2020 ; Ghoumid et al, 2017 ). Additionally, Brf1 mutations have been shown to be causative for cerebellofaciodental syndrome ( Borck et al, 2015 ; Jee et al, 2017 ; Honjo et al, 2021 ; Valenzuela et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

MAF1, a repressor of RNA polymerase III-dependent transcription, regulates bone mass

Busschers

Ahmad

Sun

et al. 2022

eLife

View full text Add to dashboard Cite

MAF1, a key repressor of RNA polymerase III-mediated transcription, has been shown to promote mesoderm formation in vitro. Here, we show that MAF1 plays a critical role in the regulation of osteoblast differentiation and bone mass. A high bone mass phenotype was noted in mice with a global deletion of Maf1 (Maf1-/- mice). However, osteoblasts isolated from Maf1-/- mice showed reduced osteoblastogenesis ex vivo. Therefore, we determined the effect of MAF1 overexpression specifically in cells from the mesenchymal lineage (Prx1-Cre;LSL-MAF1 mice). These mice showed increased bone mass. Ex vivo, cells from Prx1-Cre;LSL-MAF1 mice showed enhanced osteoblastogenesis concordant with their high bone mass phenotype. Thus, the high bone mass phenotype in Maf1-/- mice is likely due to the confounding effects of the global absence of Maf1 in Maf1-/- mice. MAF1 overexpression promoted osteoblast differentiation and shRNA-mediated Maf1 downregulation inhibited differentiation of ST2 cells, overall indicating MAF1 enhances osteoblast formation. We also found that, in contrast to MAF1 overexpression, other perturbations that repress RNA pol III transcription, including Brf1 knockdown and chemical inhibition of RNA pol III by ML-60218, inhibited osteoblast differentiation. All perturbations that decrease RNA pol III transcription, however, enhanced adipogenesis in ST2 cell cultures. RNA-seq was used to determine the basis for these opposing actions on osteoblast differentiation. The modalities used to perturb RNA pol III transcription resulted in distinct gene expression changes, indicating that this transcription process is highly sensitive and triggers diverse gene expression programs and phenotypic outcomes. Specifically, MAF1 induced genes in ST2 cells known to promote osteoblast differentiation. Furthermore, genes that are induced during osteoblast differentiation displayed codon bias. Together, these results reveal a novel role for MAF1 and RNA pol III-mediated transcription in osteoblast fate determination and differentiation and bone mass regulation.

show abstract

“…RNA Pol III is responsible for the synthesis of 5S rRNA, tRNAs, and various other small non-coding RNAs. Though thousands of small non-coding RNA in the transcriptome profile of RNA Pol III, for example, the Alu RNA, are reported to be involved in neurodegenerative diseases (Renoux and Todd, 2012 ; Sosińska et al, 2015 ; Polesskaya et al, 2018 ; Fagan et al, 2021 ), less evidence describes a direct role of RNA Pol III in the pathogenesis of diseases (Lata et al, 2021 ). There raises the question that why the mutation of RNA Pol III subunits leads to a spectrum of neuro-dysfunction.…”

Section: Rna Polymerase Mediated Transcription-coupled Dna Repairmentioning

confidence: 99%

“…As the largest and most complex RNA polymerase in eukaryotes, RNA Pol III is composed of 17 subunits. Whereas, the mutations in the subunits POLR3A, POLR3C, POLR3E, and POLR3F are associated with susceptibility to varicella zoster virus-induced encephalitis and pneumonitis, the distinct mutations in the POLR3A, POLR3B, POLR1C, and POLR3K subunits cause a spectrum of neurodegenerative diseases, which includes the most notably hypomyelination leukodystrophy (Lata et al, 2021 ). Some pathophysiological hypotheses propose that the Pol III subunit mutations impair the biogenesis of the Pol III complex and the downstream transcriptome, for example, decrease the tRNA transcripts, which further leads to a global alternation of RNA profile.…”

Section: Rna Polymerase Mediated Transcription-coupled Dna Repairmentioning

confidence: 99%

Polymerases and DNA Repair in Neurons: Implications in Neuronal Survival and Neurodegenerative Diseases

Cao

Liu

et al. 2022

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Most of the neurodegenerative diseases and aging are associated with reactive oxygen species (ROS) or other intracellular damaging agents that challenge the genome integrity of the neurons. As most of the mature neurons stay in G0/G1 phase, replication-uncoupled DNA repair pathways including BER, NER, SSBR, and NHEJ, are pivotal, efficient, and economic mechanisms to maintain genomic stability without reactivating cell cycle. In these progresses, polymerases are prominent, not only because they are responsible for both sensing and repairing damages, but also for their more diversified roles depending on the cell cycle phase and damage types. In this review, we summarized recent knowledge on the structural and biochemical properties of distinct polymerases, including DNA and RNA polymerases, which are known to be expressed and active in nervous system; the biological relevance of these polymerases and their interactors with neuronal degeneration would be most graphically illustrated by the neurological abnormalities observed in patients with hereditary diseases associated with defects in DNA repair; furthermore, the vicious cycle of the trinucleotide repeat (TNR) and impaired DNA repair pathway is also discussed. Unraveling the mechanisms and contextual basis of the role of the polymerases in DNA damage response and repair will promote our understanding about how long-lived postmitotic cells cope with DNA lesions, and why disrupted DNA repair contributes to disease origin, despite the diversity of mutations in genes. This knowledge may lead to new insight into the development of targeted intervention for neurodegenerative diseases.

show abstract

RNA Polymerase III Subunit Mutations in Genetic Diseases

Cited by 40 publications

References 266 publications

An RNA Polymerase III General Transcription Factor Engages in Cell Type-Specific Chromatin Looping

An RNA Polymerase III General Transcription Factor Engages in Cell Type-Specific Chromatin Looping

MAF1, a repressor of RNA polymerase III-dependent transcription, regulates bone mass

Polymerases and DNA Repair in Neurons: Implications in Neuronal Survival and Neurodegenerative Diseases

Contact Info

Product

Resources

About