MTERF factors: a multifunction protein family

Marina Roberti; Paola Loguercio Polosa; Francesco Bruni; Stefania Deceglie; Maria Nicola Gadaleta; Palmiro Cantatore

doi:10.1515/bmc.2010.015

MTERF factors: a multifunction protein family

BioMolecular Concepts ◽

10.1515/bmc.2010.015 ◽

2010 ◽

Vol 1 (2) ◽

pp. 215-224 ◽

Cited By ~ 5

Author(s):

Marina Roberti ◽

Paola Loguercio Polosa ◽

Francesco Bruni ◽

Stefania Deceglie ◽

Maria Nicola Gadaleta ◽

...

Keyword(s):

Transcription Initiation ◽

Leucine Zipper ◽

Protein Family ◽

Mitochondrial Genomes ◽

Modular Architecture ◽

Large Protein ◽

Mitochondrial Transcription ◽

Main Structural Feature ◽

Large Protein Family ◽

Mtdna Replication

AbstractThe MTERF family is a large protein family, identified in metazoans and plants, which consists of four subfamilies, MTERF1, 2, 3 and 4. Mitochondrial localisation was predicted for the vast majority of MTERF family members and demonstrated for the characterised MTERF proteins. The main structural feature of MTERF proteins is the presence of a modular architecture, based on repetitions of a 30-residue module, the mTERF motif, containing leucine zipper-like heptads. The MTERF family includes transcription termination factors: human mTERF, sea urchin mtDBP and Drosophila DmTTF. In addition to terminating transcription, they are involved in transcription initiation and in the control of mtDNA replication. This multiplicity of functions seems to flank differences in the gene organisation of mitochondrial genomes. MTERF2 and MTERF3 play antithetical roles in controlling mitochondrial transcription: that is, mammalian and Drosophila MTERF3 act as negative regulators, whereas mammalian MTERF2 functions as a positive regulator. Both proteins contact mtDNA in the promoter region, perhaps establishing interactions, either mutual or with other factors. Regulation of MTERF gene expression in human and Drosophila depends on nuclear transcription factors NRF-2 and DREF, respectively, and proceeds through pathways which appear to discriminate between factors positively or negatively acting in mitochondrial transcription. In this emerging scenario, it appears that MTERF proteins act to coordinate mitochondrial transcription.

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The Homeodomain Resource: a prototype database for a large protein family

Nucleic Acids Research ◽

10.1093/nar/28.1.329 ◽

2000 ◽

Vol 28 (1) ◽

pp. 329-330 ◽

Cited By ~ 8

Author(s):

S. Banerjee-Basu

Keyword(s):

Protein Family ◽

Large Protein ◽

Large Protein Family

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Claudins and the Modulation of Tight Junction Permeability

Physiological Reviews ◽

10.1152/physrev.00019.2012 ◽

2013 ◽

Vol 93 (2) ◽

pp. 525-569 ◽

Cited By ~ 584

Author(s):

Dorothee Günzel ◽

Alan S. L. Yu

Keyword(s):

Membrane Proteins ◽

Tight Junction ◽

Current Knowledge ◽

Protein Family ◽

Large Protein ◽

Physiological Functions ◽

Recent Advances ◽

Large Protein Family ◽

Tight Junction Permeability

Claudins are tight junction membrane proteins that are expressed in epithelia and endothelia and form paracellular barriers and pores that determine tight junction permeability. This review summarizes our current knowledge of this large protein family and discusses recent advances in our understanding of their structure and physiological functions.

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POLRMT regulates the switch between replication primer formation and gene expression of mammalian mtDNA

Science Advances ◽

10.1126/sciadv.1600963 ◽

2016 ◽

Vol 2 (8) ◽

pp. e1600963 ◽

Cited By ~ 40

Author(s):

Inge Kühl ◽

Maria Miranda ◽

Viktor Posse ◽

Dusanka Milenkovic ◽

Arnaud Mourier ◽

...

Keyword(s):

Gene Expression ◽

Knockout Mice ◽

Transcription Initiation ◽

Mitochondrial Gene ◽

Conditional Knockout ◽

Regulatory Role ◽

Mitochondrial Rna ◽

Mitochondrial Transcription ◽

Mtdna Replication

Mitochondria are vital in providing cellular energy via their oxidative phosphorylation system, which requires the coordinated expression of genes encoded by both the nuclear and mitochondrial genomes (mtDNA). Transcription of the circular mammalian mtDNA depends on a single mitochondrial RNA polymerase (POLRMT). Although the transcription initiation process is well understood, it is debated whether POLRMT also serves as the primase for the initiation of mtDNA replication. In the nucleus, the RNA polymerases needed for gene expression have no such role. Conditional knockout of Polrmt in the heart results in severe mitochondrial dysfunction causing dilated cardiomyopathy in young mice. We further studied the molecular consequences of different expression levels of POLRMT and found that POLRMT is essential for primer synthesis to initiate mtDNA replication in vivo. Furthermore, transcription initiation for primer formation has priority over gene expression. Surprisingly, mitochondrial transcription factor A (TFAM) exists in an mtDNA-free pool in the Polrmt knockout mice. TFAM levels remain unchanged despite strong mtDNA depletion, and TFAM is thus protected from degradation of the AAA+ Lon protease in the absence of POLRMT. Last, we report that mitochondrial transcription elongation factor may compensate for a partial depletion of POLRMT in heterozygous Polrmt knockout mice, indicating a direct regulatory role of this factor in transcription. In conclusion, we present in vivo evidence that POLRMT has a key regulatory role in the replication of mammalian mtDNA and is part of a transcriptional mechanism that provides a switch between primer formation for mtDNA replication and mitochondrial gene expression.

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Suppression of mitochondrial transcription initiation complexes changes the balance of replication intermediates of mitochondrial DNA and reduces 7S DNA in cultured human cells

The Journal of Biochemistry ◽

10.1093/jb/mvw010 ◽

2016 ◽

Vol 160 (1) ◽

pp. 49-57 ◽

Cited By ~ 1

Author(s):

Jianhua Qu ◽

Takehiro Yasukawa ◽

Dongchon Kang

Keyword(s):

Mitochondrial Dna ◽

Transcription Initiation ◽

Human Cells ◽

Mitochondrial Transcription ◽

Cultured Human Cells ◽

Replication Intermediates

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Using high-resolution annotation of insect mitochondrial DNA to decipher tandem repeats in the control region

10.1101/500330 ◽

2018 ◽

Author(s):

Ji Haishuo ◽

Xu Xiaofeng ◽

Jin Xiufeng ◽

Cheng Zhi ◽

jin Hong ◽

...

Keyword(s):

Steady State ◽

High Resolution ◽

Mitochondrial Genome ◽

Control Region ◽

Transcription Initiation ◽

Tandem Repeats ◽

Mitochondrial Gene ◽

Mitochondrial Genomes ◽

Small Rna Sequencing ◽

Antisense Gene

In this study, we used a small RNA sequencing (sRNA-seq) based method to annotate the mitochondrial genome of the insect Erthesina fullo Thunberg at 1 bp resolution. Most of the new annotations were consistent with the previous annotations which were obtained using PacBio full-length transcripts. Two important findings are that animals transcribe both entire strands of mitochondrial genomes and the tandem repeat in the control region of the E. fullo mitochondrial genome contains the repeated Transcription Initiation Sites (TISs) of the H-strand. In addition, we found that the copy numbers of tandem repeats showed a great diversity within an individual, enriching the fundamental knowledge of mitochondrial biology. This sRNA-seq based method uses 5′ and 3′ end small RNAs to annotate nuclear non-coding and mitochondrial genes at 1 bp resolution and can also be used to identify new steady-state RNAs, particularly long non-coding RNAs (lncRNAs). Animal mitochondrial genomes containing one control region only encode two steady-state lncRNAs, which are the Mitochondrial D-loop 1 (MDL1) and its antisense gene (MDL1AS), while all other reported mitochondrial lncRNAs could be degraded fragments of transient RNAs or random breaks during experimental processing. The high-resolution annotations of mitochondrial genomes can be used to study the phylogenetics and molecular evolution of animals or to investigate mitochondrial gene transcription, RNA processing, RNA maturation and several other related topics.

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Does it take two to tango? RING domain self-association and activity in TRIM E3 ubiquitin ligases

Biochemical Society Transactions ◽

10.1042/bst20200383 ◽

2020 ◽

Vol 48 (6) ◽

pp. 2615-2624

Author(s):

Filippo Fiorentini ◽

Diego Esposito ◽

Katrin Rittinger

Keyword(s):

Coiled Coil ◽

E3 Ligase ◽

Protein Family ◽

Ring Domain ◽

Cellular Functions ◽

Protein Activity ◽

Coiled Coil Region ◽

Tripartite Motif ◽

Large Protein Family ◽

Self Association

TRIM proteins form a protein family that is characterized by a conserved tripartite motif domain comprising a RING domain, one or two B-box domains and a coiled-coil region. Members of this large protein family are important regulators of numerous cellular functions including innate immune responses, transcriptional regulation and apoptosis. Key to their cellular role is their E3 ligase activity which is conferred by the RING domain. Self-association is an important characteristic of TRIM protein activity and is mediated by homodimerization via the coiled-coil region, and in some cases higher order association via additional domains of the tripartite motif. In many of the TRIM family proteins studied thus far, RING dimerization is an important prerequisite for E3 ligase enzymatic activity though the propensity of RING domains to dimerize differs significantly between different TRIMs and can be influenced by other regions of the protein.

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The Myc negative autoregulation mechanism requires Myc-Max association and involves the c-myc P2 minimal promoter.

Molecular and Cellular Biology ◽

10.1128/mcb.17.1.100 ◽

1997 ◽

Vol 17 (1) ◽

pp. 100-114 ◽

Cited By ~ 78

Author(s):

L M Facchini ◽

S Chen ◽

W W Marhin ◽

J N Lear ◽

L Z Penn

Keyword(s):

Transcription Initiation ◽

Leucine Zipper ◽

Minimal Promoter ◽

Luciferase Reporter ◽

Specific Gene ◽

Cell Type Specificity ◽

Protein Activity ◽

Binding Motifs ◽

Myc Gene ◽

Negative Autoregulation

Increasing evidence supports an important biological role for Myc in the downregulation of specific gene transcription. Recent studies suggest that c-Myc may suppress promoter activity through proteins of the basal transcription machinery. We have previously reported that Myc protein, in combination with additional cellular factors, suppresses transcription initiation from the c-myc promoter. To characterize the cis components of this Myc negative autoregulation pathway, fragments of the human c-myc promoter were inserted upstream of luciferase reporter genes and assayed for responsiveness to inducible MycER activation in Rat-1 fibroblasts. We found four- to fivefold suppression of a c-myc P2 minimal promoter fragment upon induction of wild-type MycER protein activity, while induction of a mutant MycER protein lacking amino acids 106 to 143 required for Myc autosuppression failed to elicit this response. This assay is physiologically significant, as it reflects Myc autosuppression of the endogenous c-myc gene with regard to kinetics, dose dependency, cell type specificity, and c-Myc functional domains. Analysis of mutations within the P2 minimal promoter indicated that the cis components of Myc autosuppression could not be ascribed to any known protein-binding motifs. In addition, to address the trans factors required for Myc negative autoregulation, we expressed MycEG and MaxEG leucine zipper dimerization mutants in Rat-1 cells and found that Myc-Max heterodimerization is obligatory for Myc autosuppression. Two models for the Myc autosuppression mechanism are discussed.

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Human Mitochondrial Transcription Factor B1 Interacts with the C-Terminal Activation Region of h-mtTFA and Stimulates Transcription Independently of Its RNA Methyltransferase Activity

Molecular and Cellular Biology ◽

10.1128/mcb.23.16.5816-5824.2003 ◽

2003 ◽

Vol 23 (16) ◽

pp. 5816-5824 ◽

Cited By ~ 106

Author(s):

Vicki McCulloch ◽

Gerald S. Shadel

Keyword(s):

Transcription Factor ◽

Transcriptional Activation ◽

Transcription Initiation ◽

Mitochondrial Gene ◽

Factor H ◽

Dual Function ◽

Mitochondrial Rna ◽

Methyltransferase Activity ◽

Mitochondrial Transcription

ABSTRACT A significant advancement in understanding mitochondrial gene expression is the recent identification of two new human mitochondrial transcription factors, h-mtTFB1 and h-mtTFB2. Both proteins stimulate transcription in collaboration with the high-mobility group box transcription factor, h-mtTFA, and are homologous to rRNA methyltransferases. In fact, the dual-function nature of h-mtTFB1 was recently demonstrated by its ability to methylate a conserved rRNA substrate. Here, we demonstrate that h-mtTFB1 binds h-mtTFA both in HeLa cell mitochondrial extracts and in direct-binding assays via an interaction that requires the C-terminal tail of h-mtTFA, a region necessary for transcriptional activation. In addition, point mutations in conserved methyltransferase motifs of h-mtTFB1 revealed that it stimulates transcription in vitro independently of S-adenosylmethionine binding and rRNA methyltransferase activity. Furthermore, one mutation (G65A) eliminated the ability of h-mtTFB1 to bind DNA yet did not affect transcriptional activation. These results, coupled with the observation that h-mtTFB1 and human mitochondrial RNA (h-mtRNA) polymerase can also be coimmunoprecipitated, lead us to propose a model in which h-mtTFA demarcates mitochondrial promoter locations and where h-mtTFB proteins bridge an interaction between the C-terminal tail of h-mtTFA and mtRNA polymerase to facilitate specific initiation of transcription. Altogether, these data provide important new insight into the mechanism of transcription initiation in human mitochondria and indicate that the dual functions of h-mtTFB1 can be separated.

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Characterization of mitochondrial replication and transcription control during rat early development in vivo and in vitro

Reproduction ◽

10.1530/rep-06-0263 ◽

2007 ◽

Vol 133 (2) ◽

pp. 423-432 ◽

Cited By ~ 34

Author(s):

Yuichi Kameyama ◽

France Filion ◽

Jae Gyu Yoo ◽

Lawrence C Smith

Keyword(s):

Early Development ◽

Copy Number ◽

Reproductive Technologies ◽

Blastocyst Stage ◽

Mrna Levels ◽

Mtdna Copy Number ◽

Mitochondrial Transcription ◽

Mtdna Replication

In vitroculture (IVC), used in assisted reproductive technologies, is a major environmental stress on the embryo. To evaluate the effect of IVC on mitochondrial transcription and the control of mtDNA replication, we measured the mtDNA copy number and relative amount of mRNA for mitochondrial-related genes in individual rat oocytes, zygotes and embryos using real-time PCR. The average mtDNA copy number was 147 600 (±3000) in metaphase II oocytes. The mtDNA copy number was stable throughoutin vivoearly development and IVC induced an increase in mtDNA copy number from the 8-cell stage onwards.GapdmRNA levels vary during early development and IVC did not change the patterns of these housekeeping gene transcripts.PolrmtmRNA levels did not vary during early development up to the morula stage but increased at the blastocyst stage. IVC induced the up-regulation ofPolrmtmRNA, one of the key genes regulating mtDNA transcription and replication, at the blastocyst stage. An increase inmt-Nd4mRNA preceded the blastocyst-related event observed in nuclear-encodedGapdandPolrmt, suggesting that the expression of mitochondrial encoded genes is controlled differently from nuclear encoded genes. We conclude that the IVC system can perturb mitochondrial transcription and the control of mtDNA replication in rat embryos. This perturbation of mtDNA regulation may be responsible for the abnormal physiology, metabolism and viability ofin vitro-derived embryos.

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