Methyltransferase-like protein 16 binds the 3′-terminal triple helix of MALAT1 long noncoding RNA

Brown, Jessica A.; Kinzig, Charles G.; DeGregorio, Suzanne J.; Steitz, Joan A.

doi:10.1073/pnas.1614759113

Cited by 212 publications

(224 citation statements)

References 30 publications

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“…However, S. cerevisiae does not encode a METTL16 homolog and, to our knowledge, budding yeast U6 snRNA is not methylated. Moreover, METTL16 is nuclear, consistent with a role in regulation of MAT2A splicing and U6 methylation (Brown et al, 2016). For these reasons, we explored the possibility that METTL16 methylates MAT2A and U6 snRNA.…”

Section: Resultsmentioning

confidence: 79%

“…The C. elegans and A. thaliana SAM synthetase genes have no UACAGAGAA elements, so these phenotypes are likely attributable to loss of U6 snRNA methylation, methylation of an unidentified target(s), or even other unknown functions of METTL16. In fact, while this work was under review, METTL16 was reported to bind a structured 3´-end triple helix structure of the nuclear noncoding MALAT1 RNA, apparently independent of its methyltransferase activity (Brown et al, 2016). The substrate specificities of METTL16 family members suggest that they evolved initially to be rRNA methyltransferases and subsequently were co-opted by eukaryotes to target U6 snRNA.…”

Section: Discussionmentioning

confidence: 99%

“…(D) METTL16 native RIP with extracts from cells grown for 3 hr +/−Met. Limited RNA digestion was performed and the MALAT1 amplicon is over 5 kb from the METTL16 binding site, so it serves as a negative control along with GAPDH and β-actin (Brown et al, 2016). Data are mean ± SD; n =3.…”

Section: Figurementioning

confidence: 99%

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The U6 snRNA m 6 A Methyltransferase METTL16 Regulates SAM Synthetase Intron Retention

Pendleton

Chen

Liu

et al. 2017

Cell

821

1,017

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SUMMARY Maintenance of proper levels of the methyl donor S-adenosylmethionine (SAM) is critical for a wide variety of biological processes. We demonstrate that the N6-adenosine methyltransferase METTL16 regulates expression of human MAT2A, which encodes the SAM synthetase expressed in most cells. Upon SAM depletion by methionine starvation, cells induce MAT2A expression by enhanced splicing of a retained intron. Induction requires METTL16 and its methylation substrate, a vertebrate conserved hairpin (hp1) in the MAT2A 3´ UTR. Increasing METTL16 occupancy on the MAT2A 3´ UTR is sufficient to induce efficient splicing. We propose that under SAM-limiting conditions, METTL16 occupancy on hp1 increases due to inefficient enzymatic turnover, which promotes MAT2A splicing. We further show that METTL16 is the long-unknown methyltransferase for the U6 spliceosomal snRNA. These observations suggest that the conserved U6 snRNA methyltransferase evolved an additional function in vertebrates to regulate SAM homeostasis.

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Section: Resultsmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The U6 snRNA m 6 A Methyltransferase METTL16 Regulates SAM Synthetase Intron Retention

Pendleton

Chen

Liu

et al. 2017

Cell

821

1,017

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show abstract

“…However, several questions remain to be answered: for example, does the triple helix structure have additional functions besides regulating RNA stability; what is the function of the tRNA-like structure; does it only provide an RNase P cleavage site to produce lncRNAs with a triple helix 3′-tail. The recent identification of one MALAT1 triplex-interacting protein, RNA methyltransferase-like protein 16 (METTL16), suggests the existence of a class of triple-stranded RNA binding proteins (Brown et al, 2016). Future identification of additional proteins associated with the triple-helix and tRNA-like structures will provide further functional insights.…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of a Class of MALAT1-like Genomic Loci

Zhang¹,

Mao²,

Diermeier³

et al. 2017

Cell Reports

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The MALAT1 (Metastasis-Associated Lung Adenocarcinoma Transcript 1) gene encodes a non-coding RNA that is processed into a long nuclear retained transcript (MALAT1) and a small cytoplasmic tRNA-like transcript (mascRNA). Using a RNA sequence- and structure-based covariance model, we identified more than 130 genomic loci in vertebrate genomes containing the MALAT1 3′-end triple helix structure and its immediate downstream tRNA-like structure, including 44 in the green lizard Anolis carolinensis. Structural and computational analyses revealed a coevolution of the 3′-end module. MALAT1-like genes in Anolis carolinensis are highly expressed in adult testis, thus we named them testis-abundant long noncoding RNAs (tancRNAs). MALAT1-like loci also produce multiple small RNA species, including piRNAs, from the antisense strand. The coevolved 3′-ends of tancRNAs serve as potential targets for the PIWI-piRNA complex. Thus, we have identified an evolutionarily conserved class of lncRNAs with similar structural constraints, post-transcriptional processing, subcellular localization and a distinct function in spermatocytes.

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“…This binding happens via a triple RNA binding helix element as Brown et al 168 have observed. MALAT1 is a long non coding RNA whose 3' functional motiff plays a role in the cell proliferation, invasion and metastasis in CRC 169 .…”

Section: Dicationmentioning

confidence: 89%

Revealing ETC-1922159 Affected Unknown 3<em><sup>rd</sup></em> order WNT10B-X-X Combinations, in Silico

Sinha¹

2017

Preprint

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WNT10B belongs to the family of WNT proteins that are implicated in a range of phenomena that are affected by the Wnt signaling pathway. Recent studies have shown that WNT10B plays a role in colorectal cancer. WNTs have been found to directly affect the stemness of the tumor cells via regulation of ASCL2. Switching off the ASCL2 literally blocks the stemness process of the tumor cells and vice versa. Furthermore, recent findings suggest BVES to be highly suppressed in malignancies and in vitro deletions of BVES show higher Wnt signaling activity to induce stemness. WNT10B was found to be highly expressed in such cases. Often, in biology, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combination of factors that might be affecting the pathway under certain conditions. For example, WNT10B-ASCL2 is one such 2 nd order combination whose relation needs to be tested under the influence of recently developed porcupine-WNT inhibitor ETC-1922159. The inhibitor is known to suppress PORCN (porcupine) and thus inhibit a range of oncogenes known to be directly or indirectly affected by the Wnts. In a recent unpublished work in bioRxiv, Sinha 1 , we had the opportunity to rank these unknown biological hypotheses for down regulated genes at 2 nd order level after the drug was administered. The in silico observations showed that the combination of WNT10B-ASCL2 was assigned a relatively lower rank, thus validating the pipeline's efficacy with the confirmed wet lab experiment that indicate that both WNT10B and ASCL2 were down regulated after treatment in cancer cells. Here, we take one step further by in silico analysis of the 3 rd order combinations of WNT10B-X-X (X can be known or unknown factor), from a range of 100 randomly picked down regulated genes after ETC-1922159 treatment. The pipeline uses the density based HSIC (Hilbert Schmidt Information Criterion) sensitivity index with an rbf (radial basis function) kernel, which is known to be highly effective in sensitivity analysis. Various unknown/unexplored/untested 3 rd order biological hypotheses emerge some of which are confirmed in wet lab, while others need to be tested. The potential of such ranking is indispensable in the current era of search in a vast combinatorial forest. KEYWORDS -WNT pathway; porcupine inhibitor ETC-1922159; sensitivity analysis; colorectal cancer; unknown biological hypotheses; combinatorial search space; support vector ranking Conference, from 6-11 August 2017, held Significance WNT10B belongs to the family of WNT proteins that are implicated in a range of phenomena that are affected by the Wnt signaling pathway. Recent studies have shown that WNT10B plays a role in colorectal cancer. Often, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combination of factors that might be involved in the pathway. The current work reveals at in silico level, the 3rd order WNT10B associated combinations that might be affected by the admin...

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Methyltransferase-like protein 16 binds the 3′-terminal triple helix of MALAT1 long noncoding RNA

Cited by 212 publications

References 30 publications

The U6 snRNA m 6 A Methyltransferase METTL16 Regulates SAM Synthetase Intron Retention

The U6 snRNA m 6 A Methyltransferase METTL16 Regulates SAM Synthetase Intron Retention

Identification and Characterization of a Class of MALAT1-like Genomic Loci

Revealing ETC-1922159 Affected Unknown 3<em><sup>rd</sup></em> order WNT10B-X-X Combinations, in Silico

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