The Distinct Function and Localization of METTL3/METTL14 and METTL16 Enzymes in Cardiomyocytes

Arcidiacono, Orazio Angelo; Krejčí, Jana; Bártová, Eva

doi:10.3390/ijms21218139

Cited by 17 publications

(11 citation statements)

References 55 publications

(84 reference statements)

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“…We have recently shown distinctions between METTL3/METTL14 and METTL16 proteins in embryonic stem cells (ESCs) experimentally stimulated into cardiomyocytes. We have also observed that the nuclear pools and nuclear distribution of METTL3/METTL14 proteins in mouse ESCs were different from those studied in METTL16 [ 33 ]. Ruszkowska et al [ 11 ] also showed that the molecular structure of METTL16 is different from the structure of METTL3 and METTL14 proteins.…”

Section: Discussionmentioning

confidence: 99%

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Localization of METTL16 at the Nuclear Periphery and the Nucleolus Is Cell Cycle-Specific and METTL16 Interacts with Several Nucleolar Proteins

Stixová

Komůrková

Kovaříková

et al. 2021

Life

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METTL16 methyltransferase is responsible for the methylation of N6-adenosine (m6A) in several RNAs. In mouse cells, we showed that the nuclear distribution of METTL16 is cell cycle-specific. In the G1/S phases, METTL16 accumulates to the nucleolus, while in the G2 phase, the level of METTL16 increases in the nucleoplasm. In metaphase and anaphase, there is a very low pool of the METTL16 protein, but in telophase, residual METTL16 appears to be associated with the newly formed nuclear lamina. In A-type lamin-depleted cells, we observed a reduction of METTL16 when compared with the wild-type counterpart. However, METTL16 does not interact with A-type and B-type lamins, but interacts with Lamin B Receptor (LBR) and Lap2α. Additionally, Lap2α depletion caused METTL16 downregulation in the nuclear pool. Furthermore, METTL16 interacted with DDB2, a key protein of the nucleotide excision repair (NER), and also with nucleolar proteins, including TCOF, NOLC1, and UBF1/2, but not fibrillarin. From this view, the METTL16 protein may also regulate the transcription of ribosomal genes because we observed that the high level of m6A in 18S rRNA appeared in cells with upregulated METTL16.

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Section: Discussionmentioning

confidence: 99%

“…Moreover, in mouse 16-cell embryos, characterized by Mettl16 depletion, it was found that the mRNA level was reduced. This observation indicates that METTL16 plays a role in early development and, therefore, cell differentiation [ 17 , 33 ].…”

Section: Discussionmentioning

confidence: 99%

Localization of METTL16 at the Nuclear Periphery and the Nucleolus Is Cell Cycle-Specific and METTL16 Interacts with Several Nucleolar Proteins

Stixová

Komůrková

Kovaříková

et al. 2021

Life

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“… 160 The expression of METTL3 and METTL14, as well as the abundance of m 6 A in RNAs, are evenly distributed in embryonic hearts, and their expression is increased by the histone deacetylase inhibitors valproic acid and Trichostatin A. 159 …”

Section: N 6 -Methyladenosine and A-to-i Modificat...mentioning

confidence: 99%

Emerging roles of the RNA modifications N6-methyladenosine and adenosine-to-inosine in cardiovascular diseases

Sikorski¹,

Vento²,

Kankuri³

2022

Molecular Therapy - Nucleic Acids

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“…The transcriptome data also reflects the importance of epigenetic changes elicited by MPP+ in both CV and LDH-A/B DKOs, evidenced by the sheer number of downregulated histone cluster transcripts as well as the massive bidirectional DEGs in non-protein coding microRNA and long-intergenic transcripts. MPP+ also evoked changes in a number of METTL transcripts, which are believed to contribute to nucleoside modifications in diverse types of RNA and DNA (86,87), however very little is known on these particular epigenetic modifications.…”

Section: Table II David Functional Annotation Pathway Analysis Of Up-regulated Degs Caused By Mpp+ When Comparing Controls Vs Controls + mentioning

confidence: 99%

Metabolic Response to the Mitochondrial Toxin 1-Methyl-4-phenylpyridinium (MPP+) in LDH-A/B Double-knockout LS174T Colon Cancer Cells

Mack

Mazzio

Badisa

et al. 2021

Cancer Genomics Proteomics

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Background/Aim: Rapid glycolytic substrate-level phosphorylation (SLP) and accumulation of lactic acid are characteristics of diverse cancers. Recent advances in drug discovery have included the use of glycolytic inhibitors with mitochondrial targeting drugs to attempt to invoke an energy crisis in aggressive metabolically active chemo-resistant cancers. In this work, we examine the consequences of inhibiting mitochondrial oxidative phosphorylation (OXPHOS) with 1-methyl-4-phenylpyridinium (MPP+) in LS14T colon cancer cells containing a genetic double knock out (DKO) of lactic acid dehydrogenase (LDHA and LDHB). Materials and Methods: Several metabolic parameters were evaluated concomitant to whole transcriptomic (WT) mRNA, microRNA, and long intergenic non-coding RNAs using Affymetrix 2.1 human ST arrays. Results: MPP+ effectively blocked OXPHOS where a compensatory shift toward anaerobic SLP was only observed in the control vector (CV), and not observed in the LDH-A/B DKOs (lacking the ability to produce lactic acid). Despite this, there was an unexpected resilience to MPP+ in the latter in terms of energy, which displayed significantly higher resting baseline respiratory OXPHOS capacity relative to controls. At the transcriptome level, MPP+ invoked 1738 differential expressed genes (DEGs) out of 48,226; LDH-A/B DKO resulted in 855 DEGs while 349 DEGs were found to be overlapping in both groups versus respective controls, including loss of mitochondrial complex I (subunits 3 and 6), cell cycle transcripts and fluctuations in epigenetic chromatin remodeling systems. In terms of energy, the effects of MPP+ in the CV transcripts reflect the funneling of carbon intermediates toward glycolysis. The LDH-A/B DKO transcripts reflect a flow of carbons away from glycolysis toward the production of acetyl-CoA. Conclusion: The findings from this study suggest a metabolic resilience to MPP+ in cancer cells devoid of LDH-A/B, explainable in-part by higher baseline OXPHOS respiratory ATP production, necessitating more toxin to suppress the electron transport chain.

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The Distinct Function and Localization of METTL3/METTL14 and METTL16 Enzymes in Cardiomyocytes

Cited by 17 publications

References 55 publications

Localization of METTL16 at the Nuclear Periphery and the Nucleolus Is Cell Cycle-Specific and METTL16 Interacts with Several Nucleolar Proteins

Localization of METTL16 at the Nuclear Periphery and the Nucleolus Is Cell Cycle-Specific and METTL16 Interacts with Several Nucleolar Proteins

Emerging roles of the RNA modifications N6-methyladenosine and adenosine-to-inosine in cardiovascular diseases

Metabolic Response to the Mitochondrial Toxin 1-Methyl-4-phenylpyridinium (MPP+) in LDH-A/B Double-knockout LS174T Colon Cancer Cells

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