The human 18S rRNA m6A methyltransferase METTL5 is stabilized by TRMT112

Tran, Nhan van; Ernst, Felix G.M.; Hawley, Ben R; Zorbas, Christiane; Ulryck, Nathalie; Hackert, Philipp; Bohnsack, Katherine E.; Bohnsack, Markus T.; Jaffrey, Samie R.; Graille, Marc; Lafontaine, Denis L. J.

doi:10.1093/nar/gkz619

Cited by 359 publications

(402 citation statements)

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“…2A), which was shown to be TRMT12 by Western blotting (Fig. S2A), which is consistent with the previous report (31). Furthermore, untagged, endogenous METTL5 also co-immunoprecipitates (co-IP) TRMT112, and reciprocally, TRMT112 antibodies brought down considerable amount of endogenous METTL5 (Fig.…”

Section: Trmt112 Is a Partner Of Mettl5 And Is Important For Mettl5 Asupporting

confidence: 91%

“…2E), consistent with the notion that METTL5-TRMT112 specifically mediates methylation of 18S rRNA. A recent independent study also reported TRMT112 as METTL5 partner, and that the METTL5 catalytic activity in vivo requires TRMT112 (31). Somewhat surprisingly, van Tran et al failed to observe in vitro activity of the METTL5-TRMT112 heterodimer on short RNA oligonucleotides corresponding to the sequences surrounding A1832 in the mature ribosome (31).…”

Section: Trmt112 Is a Partner Of Mettl5 And Is Important For Mettl5 Amentioning

confidence: 99%

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METTL5, an 18S rRNA-specific m⁶A methyltransferase, modulates expression of stress response genes

Chen

Liu

et al. 2020

Preprint

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Tel. (617)919-3100.Running title: m 6 A on 18S rRNA is important for selective mRNA translation Abstract RNA N 6 -methyladenosine (m 6 A) modification is present in different RNA molecules, including protein-coding mRNAs and non-coding RNAs such as ribosomal RNAs (rRNAs). Previous studies identified m 6 A in both the 18S and 28S rRNAs, but the roles of these methylation events are poorly understood due to the lack of knowledge of the responsible methyltransferases. Here, we report that mammalian METTL5, a member of a highly conserved methyltransferase family, specifically methylates adenosine 1832 (A1832) in the 18S rRNA in vivo and in vitro. We identify TRMT112 as a near stoichiometric partner of METTL5 important for the enzymatic activity of METTL5. By mapping the positions of translating ribosomes (Ribo-seq), we found translation of multiple stress response-related mRNAs, including Atf4 mRNA, is selectively reduced in the Mettl5 knockout (KO) mouse B16 melanoma cells. Atf4 is a key transcription factor that mediates the Integrated Stress Response (ISR), as exemplified by the Endoplasmic Reticulum (ER) stress. Consistently, transcription of ISR effector genes is reduced in Mettl5 KO cells during ER stress, suggesting a compromised ISR. Our findings reveal a new mechanism that regulates expression of stress response genes and suggest that chemical modifications of ribosomal RNAs may play a key role in selectively impacting translation and possibly ISR.

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Section: Trmt112 Is a Partner Of Mettl5 And Is Important For Mettl5 Asupporting

confidence: 91%

Section: Trmt112 Is a Partner Of Mettl5 And Is Important For Mettl5 Amentioning

confidence: 99%

METTL5, an 18S rRNA-specific m⁶A methyltransferase, modulates expression of stress response genes

Chen

Liu

et al. 2020

Preprint

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“…Whether METTL5 methylates the same residue on the 18S and whether it plays a conserved role in regulating the stress response and translation of cytochrome P450 enzymes remain to be seen. Human METTL5 seems to require binding of the methyltransferase activator TRMT112 to be stabilized (17). However, we found that the worm ortholog of TRMT112, C04H5.1, was dispensable for METL-5 stability and activity.…”

Section: Discussionmentioning

confidence: 64%

N6-adenosine methylation of ribosomal RNA affects lipid oxidation and stress resistance

et al. 2020

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During stress, global translation is reduced, but specific transcripts are actively translated. How stress-responsive mRNAs are selectively translated is unknown. We show that METL-5 methylates adenosine 1717 on 18S ribosomal RNA in C. elegans, enhancing selective ribosomal binding and translation of specific mRNAs. One of these mRNAs, CYP-29A3, oxidizes the omega-3 polyunsaturated fatty acid eicosapentaenoic acid to eicosanoids, key stress signaling molecules. While metl-5–deficient animals grow normally under homeostatic conditions, they are resistant to a variety of stresses. metl-5 mutant worms also show reduced bioactive lipid eicosanoids and dietary supplementation of eicosanoid products of CYP-29A3 restores stress sensitivity of metl-5 mutant worms. Thus, methylation of a specific residue of 18S rRNA by METL-5 selectively enhances translation of cyp-29A3 to increase production of eicosanoids, and blocking this pathway increases stress resistance. This study suggests that ribosome methylation can facilitate selective translation, providing another layer of regulation of the stress response.

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“…Recently, two m6A rRNA methyltransferases, Mettl5 and ZCCHC4, were discovered. They are responsible for m6A modification of 18S and 28S rRNA, respectively, which influence on ribosome assembly, translation, and finally cell proliferation [25,26].…”

Section: Introductionmentioning

confidence: 99%

Modification of Adenosine196 by Mettl3 Methyltransferase in the 5’-External Transcribed Spacer of 47S Pre-rRNA Affects rRNA Maturation

Sergeeva

Sergeev

Melnikov

et al. 2020

Cells

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Ribosome biogenesis is among the founding processes in the cell. During the first stages of ribosome biogenesis, polycistronic precursor of ribosomal RNA passes complex multistage maturation after transcription. Quality control of preribosomal RNA (pre-rRNA) processing is precisely regulated by non-ribosomal proteins and structural features of pre-rRNA molecules, including modified nucleotides. However, many participants of rRNA maturation are still unknown or poorly characterized. We report that RNA m6A methyltransferase Mettl3 interacts with the 5′ external transcribed spacer (5′ETS) of the 47S rRNA precursor and modifies adenosine 196. We demonstrated that Mettl3 knockdown results in the increase of pre-rRNA processing rates, while intracellular amounts of rRNA processing machinery components (U3, U8, U13, U14, and U17 small nucleolar RNA (snoRNA)and fibrillarin, nucleolin, Xrn2, and rrp9 proteins), rRNA degradation rates, and total amount of mature rRNA in the cell stay unchanged. Increased efficacy of pre-rRNA cleavage at A’ and A0 positions led to the decrease of 47S and 45S pre-rRNAs in the cell and increase of mature rRNA amount in the cytoplasm. The newly identified conserved motif DRACH sequence modified by Mettl3 in the 5′-ETS region is found and conserved only in primates, which may suggest participation of m6A196 in quality control of pre-rRNA processing at initial stages demanded by increased complexity of ribosome biogenesis.

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The human 18S rRNA m6A methyltransferase METTL5 is stabilized by TRMT112

Cited by 359 publications

References 77 publications

METTL5, an 18S rRNA-specific m⁶A methyltransferase, modulates expression of stress response genes

METTL5, an 18S rRNA-specific m⁶A methyltransferase, modulates expression of stress response genes

N6-adenosine methylation of ribosomal RNA affects lipid oxidation and stress resistance

Modification of Adenosine196 by Mettl3 Methyltransferase in the 5’-External Transcribed Spacer of 47S Pre-rRNA Affects rRNA Maturation

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The human 18S rRNA m6A methyltransferase METTL5 is stabilized by TRMT112

Cited by 359 publications

References 77 publications

METTL5, an 18S rRNA-specific m6A methyltransferase, modulates expression of stress response genes

METTL5, an 18S rRNA-specific m6A methyltransferase, modulates expression of stress response genes

N6-adenosine methylation of ribosomal RNA affects lipid oxidation and stress resistance

Modification of Adenosine196 by Mettl3 Methyltransferase in the 5’-External Transcribed Spacer of 47S Pre-rRNA Affects rRNA Maturation

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METTL5, an 18S rRNA-specific m⁶A methyltransferase, modulates expression of stress response genes

METTL5, an 18S rRNA-specific m⁶A methyltransferase, modulates expression of stress response genes