Phosphorylation of mitochondrial transcription factor B2 controls mitochondrial DNA binding and transcription

Bostwick, Alicia M.; Moya, Gonzalo E.; Senti, Mackenna; Basu, Urmimala; Shen, Jiayu; Patel, Smita S.; Dittenhafer‐Reed, Kristin E.

doi:10.1016/j.bbrc.2020.05.141

Cited by 4 publications

(7 citation statements)

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“…Tfb2m encodes mitochondrial transcription factor B2 ( TFB2m ) protein that is a critical regulator in control mitochondrial DNA (mtDNA) transcription and production of mitochondria-encoded proteins. TFB2m melts the mtDNA helix at the promoter region to allow mitochondrial RNA polymerase ( Polrmt ) to initiate transcription from the mtDNA template .…”

Section: Resultsmentioning

confidence: 99%

“…TFB2m melts the mtDNA helix at the promoter region to allow mitochondrial RNA polymerase (Polrmt) to initiate transcription from the mtDNA template. 20 TFB2m gene is upregulated in HCC, and the protein promotes the HCC cell proliferation, metastasis, and migration. 21 Inhibition of TFB2m transcription by ph−ph + could downregulate mitochondrialencoded protein expression and then reduce mitochondrial respiratory chain complexes' activities, leading to energy depletion (Figure 4E).…”

Section: ■ Resultsmentioning

confidence: 99%

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Synthesis of Hemiprotonic Phenanthroline–Phenanthroline⁺ Compounds with both Antitumor and Antimicrobial Activity

Zhao

Cui

et al. 2022

J. Med. Chem.

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Currently, cancer patients with microbial infection are a severe challenge in clinical treatment. To address the problem, we synthesized hemiprotonic compounds based on the unique structure of hemiprotonic nucleotide base pairs in a DNA i-motif. These compounds were produced from phenanthroline (ph) dimerization with phenanthroline as a proton receptor and ammonium as a donor. The biological activity shows that the compounds have a selective antitumor effect through inducing cell apoptosis. The molecular mechanism could be related to specific inhibition of transcription factor PLAGL2 of tumor cells, assessed by transcriptomic analysis. Moreover, results show that the hemiprotonic ph–ph+ has broad-spectrum antibacterial and antifungal activities, and drug-resistant bacteria, including methicillin-resistant Staphylococcus aureus, are sensitive to the compound. In animal models of liver cancer with fungal infection, the ph–ph+ retards proliferation of hepatoma cells in tumor-bearing mice and remedies pneumonia and encephalitis caused by Cryptococcus neoformans. The study provides a novel therapeutic candidate for cancer patients accompanied by infection.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Resultsmentioning

confidence: 99%

Synthesis of Hemiprotonic Phenanthroline–Phenanthroline⁺ Compounds with both Antitumor and Antimicrobial Activity

Zhao

Cui

et al. 2022

J. Med. Chem.

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“…TFB2M is a protein necessary for promoter melting at transcription initiation [ 92 ] and has three phosphorylation sites, namely, threonine 184, serine 197, and threonine 313. Alicia M. Bostwick [ 93 ] found that the phosphorylation of these sites impairs promoter binding and prevents transcription.…”

Section: Mitochondrial Epigenetic Changes In Admentioning

confidence: 99%

Targeted Mitochondrial Epigenetics: A New Direction in Alzheimer’s Disease Treatment

Song

Zhu

Zhang

et al. 2022

IJMS

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Mitochondrial epigenetic alterations are closely related to Alzheimer’s disease (AD), which is described in this review. Reports of the alteration of mitochondrial DNA (mtDNA) methylation in AD demonstrate that the disruption of the dynamic balance of mtDNA methylation and demethylation leads to damage to the mitochondrial electron transport chain and the obstruction of mitochondrial biogenesis, which is the most studied mitochondrial epigenetic change. Mitochondrial noncoding RNA modifications and the post-translational modification of mitochondrial nucleoproteins have been observed in neurodegenerative diseases and related diseases that increase the risk of AD. Although there are still relatively few mitochondrial noncoding RNA modifications and mitochondrial nuclear protein post-translational modifications reported in AD, we have reason to believe that these mitochondrial epigenetic modifications also play an important role in the AD process. This review provides a new research direction for the AD mechanism, starting from mitochondrial epigenetics. Further, this review summarizes therapeutic approaches to targeted mitochondrial epigenetics, which is the first systematic summary of therapeutic approaches in the field, including folic acid supplementation, mitochondrial-targeting antioxidants, and targeted ubiquitin-specific proteases, providing a reference for therapeutic targets for AD.

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“…Like TFAM, TFB2M is also phosphorylated. Phosphorylation of TFB2M on two key threonine residues decreases the binding affinity of TFB2M for both mitochondrial promoters and its ability to carry out transcription in vitro ( 166 ). These phosphorylation sites are proposed to interact with the thumb domain of h-mtRNAP, thereby interfering with key interactions between TFB2M and h-mtRNAP and attenuating transcription initiation.…”

Section: Regulation Of Mitochondrial Transcriptionmentioning

confidence: 99%

Structure, mechanism, and regulation of mitochondrial DNA transcription initiation

Basu

Bostwick

Das

et al. 2020

Journal of Biological Chemistry

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Mitochondria are specialized compartments that produce requisite ATP to fuel cellular functions and serve as centers of metabolite processing, cellular signaling, and apoptosis. To accomplish these roles, mitochondria rely on the genetic information in their small genome (mitochondrial DNA) and the nucleus. A growing appreciation for mitochondria's role in a myriad of human diseases, including inherited genetic disorders, degenerative diseases, inflammation, and cancer, has fueled the study of biochemical mechanisms that control mitochondrial function. The mitochondrial transcriptional machinery is different from nuclear machinery. The in vitro reconstituted transcriptional complexes of Saccharomyces cerevisiae (yeast) and humans, aided with high-resolution structures and biochemical characterizations, have provided a deeper understanding of the mechanism and regulation of mitochondrial DNA transcription. In this review, we will discuss recent advances in the structure and mechanism of mitochondrial transcription initiation. We will follow up with recent discoveries and formative findings regarding the regulatory events that control mitochondrial DNA transcription, focusing on those involved in crosstalk between the mitochondria and nucleus.

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Phosphorylation of mitochondrial transcription factor B2 controls mitochondrial DNA binding and transcription

Cited by 4 publications

References 23 publications

Synthesis of Hemiprotonic Phenanthroline–Phenanthroline⁺ Compounds with both Antitumor and Antimicrobial Activity

Synthesis of Hemiprotonic Phenanthroline–Phenanthroline⁺ Compounds with both Antitumor and Antimicrobial Activity

Targeted Mitochondrial Epigenetics: A New Direction in Alzheimer’s Disease Treatment

Structure, mechanism, and regulation of mitochondrial DNA transcription initiation

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Phosphorylation of mitochondrial transcription factor B2 controls mitochondrial DNA binding and transcription

Cited by 4 publications

References 23 publications

Synthesis of Hemiprotonic Phenanthroline–Phenanthroline+ Compounds with both Antitumor and Antimicrobial Activity

Synthesis of Hemiprotonic Phenanthroline–Phenanthroline+ Compounds with both Antitumor and Antimicrobial Activity

Targeted Mitochondrial Epigenetics: A New Direction in Alzheimer’s Disease Treatment

Structure, mechanism, and regulation of mitochondrial DNA transcription initiation

Contact Info

Product

Resources

About

Synthesis of Hemiprotonic Phenanthroline–Phenanthroline⁺ Compounds with both Antitumor and Antimicrobial Activity

Synthesis of Hemiprotonic Phenanthroline–Phenanthroline⁺ Compounds with both Antitumor and Antimicrobial Activity