The m6A-methylase complex recruits TREX and regulates mRNA export

Lesbirel, Simon; Viphakone, Nicolas; Parker, Matthew; Parker, Jacob; Heath, Catherine G.; Sudbery, Ian; Wilson, Stuart A.

doi:10.1038/s41598-018-32310-8

Cited by 96 publications

(93 citation statements)

References 61 publications

(85 reference statements)

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“…VIRMA is important for the proper establishment of the cellular m 6 A profile [33] and, indeed, its knockdown in the metastatic androgen-independent PC-3 cells led to significant m 6 A reduction. Recently, similar results were reported for METTL3 silencing in PCa cell lines [34].…”

Section: Discussionmentioning

confidence: 97%

VIRMA-Dependent N6-Methyladenosine Modifications Regulate the Expression of Long Non-Coding RNAs CCAT1 and CCAT2 in Prostate Cancer

Barros‐Silva

Lobo

Guimarães‐Teixeira

et al. 2020

Cancers

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RNA methylation at position N6 in adenosine (m6A) and its associated methyltransferase complex (MTC) are involved in tumorigenesis. We aimed to explore m6A biological function for long non-coding RNAs (lncRNAs) in prostate cancer (PCa) and its clinical significance. m6A and MTC levels in PCa cells were characterized by ELISA and western blot. Putative m6A-regulated lncRNAs were identified and validated by lncRNA profiler qPCR array and bioinformatics analysis, followed by m6A/RNA co-immunoprecipitation. Impact of m6A depletion on RNA stability was assessed by Actinomycin D assay. The association of m6A-levels with PCa prognosis was examined in clinical samples. Higher m6A-levels and VIRMA overexpression were detected in metastatic castration-resistant PCa (mCRPC) cells (p < 0.05). VIRMA knockdown in PC-3 cells significantly decreased m6A-levels (p = 0.0317), attenuated malignant phenotype and suppressed the expression of oncogenic lncRNAs CCAT1 and CCAT2 (p < 0.00001). VIRMA depletion and m6A reduction decreased the stability and abundance of CCAT1/2 transcripts. Higher expression of VIRMA, CCAT1, and CCAT2 as a group variable was an independent predictor of poor prognosis (HR = 9.083, CI95% 1.911–43.183, p = 0.006). VIRMA is a critical factor sustaining m6A-levels in PCa cells. VIRMA downregulation attenuates the aggressive phenotype of PCa by overall reduction of m6A-levels decreasing stability and abundance of oncogenic lncRNAs.

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Section: Discussionmentioning

confidence: 97%

VIRMA-Dependent N6-Methyladenosine Modifications Regulate the Expression of Long Non-Coding RNAs CCAT1 and CCAT2 in Prostate Cancer

Barros‐Silva

Lobo

Guimarães‐Teixeira

et al. 2020

Cancers

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“…However, long internal exons and 3' UTRs do not have an EJC in their vicinity. YTHDC1 can compensate for the absence of an EJC in these regions by binding nearby m 6 A sites and mediate the recruitment of the TREX complex to promote nuclear export 141 .…”

Section: A Enhances Nuclear Exportmentioning

confidence: 99%

The m⁶A Writer: Rise of a Machine for Growing Tasks

2018

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The central dogma of molecular biology introduced by Crick describes a linear flow of information from DNA to mRNA to protein. Since then it has become evident that RNA undergoes several maturation steps such as capping, splicing, 3'-end processing and editing. Likewise, nucleotide modifications are common in mRNA and are present in all organisms impacting on the regulation of gene expression. The most abundant modification found in mRNA is N6-methyladenosine (m 6 A). Deposition of m 6 A is a nuclear process and is performed by a megadalton writer complex primarily on mRNAs, but also on microRNAs and lncRNAs. The m 6 A methylosome is composed of the enzymatic core components METTL3 and METTL14, and several auxiliary proteins necessary for its correct positioning and functioning, which are WTAP, VIRMA, FLACC, RBM15 and HAKAI. The m 6 A epimark is decoded by YTH domain containing reader proteins YTHDC and YTHDF, but METTLs can act as 'readers' as well. Eraser proteins, such as FTO and ALKBH5, can remove the methyl group. Here we review recent progress on the role of m 6 A in regulating gene expression in light of Crick's central dogma of molecular biology. In particular, we address the complexity of the writer complex from an evolutionary perspective to obtain insights into the mechanism of ancient m 6 A methylation and its regulation.

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“…Several prominent protein bands were detected in an anti-THOC7 immune-pellet ( Figure 1a). The THO components, including hHpr1 (THOC1), THOC2 and THOC5, as well as the known THO-interacting proteins, such as ALYREF (data not shown; see Katahira et al, 2013), CPSF6 (Katahira et al, 2013), CHTOP (Chang et al, 2013), YTHDC1 (Lesbirel et al, 2018) and CBP80 (NCBP1; Cheng et al, 2006), were identified by mass spectrometric analysis (Supporting information Table S1). In addition, the 5′-3′ exonuclease XRN2, which is involved in RNAP II termination (Proudfoot, 2016;West et al, 2004), was identified as a novel hTHOinteracting factor.…”

Section: Identification Of Htho-interacting Proteinsmentioning

confidence: 99%

Human THO coordinates transcription termination and subsequent transcript release from the HSP70 locus

et al. 2019

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A multiprotein complex, THO/TREX, couples the transcription, 3′‐end formation and nuclear export of mRNAs. In this study, we report that crucial factors for mRNA processing, such as XRN2, DDX5/DDX17 and CstF64, are copurified with human THO (hTHO). Using chromatin immunoprecipitation, we found increased cross‐linking of XRN2 and CstF64 to the RNA polymerase II (RNAP II) pause site of the HSPA1A gene upon down‐regulation of THOC5, a metazoan‐specific component of hTHO. As observed in THOC5‐depleted cells, knockdown of XRN2 blocked HSP70 transcript release and increased the amount of CstF64 at the pause site. In addition, our data indicate that DDX5/DDX17 is also required for HSP70 transcript release. As the degradation of read‐through transcripts, but not cleavage at polyadenylation sites per se, was hindered upon THOC5 or DDX5/DDX17 down‐regulation, these factors appear to influence transcriptional termination. Interestingly, over‐expression of RNase H suppressed the accumulation of HSP70 transcripts in nuclear foci in THOC5‐ or DDX5/DDX17‐depleted cells. Thus, we propose a model in which hTHO, along with DDX5/DDX17, restricts the formation of R‐loops, thereby facilitating the XRN2‐mediated transcriptional termination and release of the mature transcript from the HSPA1A locus.

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The m6A-methylase complex recruits TREX and regulates mRNA export

Cited by 96 publications

References 61 publications

VIRMA-Dependent N6-Methyladenosine Modifications Regulate the Expression of Long Non-Coding RNAs CCAT1 and CCAT2 in Prostate Cancer

VIRMA-Dependent N6-Methyladenosine Modifications Regulate the Expression of Long Non-Coding RNAs CCAT1 and CCAT2 in Prostate Cancer

The m⁶A Writer: Rise of a Machine for Growing Tasks

Human THO coordinates transcription termination and subsequent transcript release from the HSP70 locus

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The m6A-methylase complex recruits TREX and regulates mRNA export

Cited by 96 publications

References 61 publications

VIRMA-Dependent N6-Methyladenosine Modifications Regulate the Expression of Long Non-Coding RNAs CCAT1 and CCAT2 in Prostate Cancer

VIRMA-Dependent N6-Methyladenosine Modifications Regulate the Expression of Long Non-Coding RNAs CCAT1 and CCAT2 in Prostate Cancer

The m6A Writer: Rise of a Machine for Growing Tasks

Human THO coordinates transcription termination and subsequent transcript release from the HSP70 locus

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The m⁶A Writer: Rise of a Machine for Growing Tasks