The 18S rRNA Methyltransferase DIMT-1 Regulates Lifespan in the Germline Later in Life
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ABSTRACT:
PROVIDER: PRJNA996637 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25345022_1.fastq.gz | Fastqsanger.gz | |||
| SRR25345022_2.fastq.gz | Fastqsanger.gz | |||
| SRR25345023_1.fastq.gz | Fastqsanger.gz | |||
| SRR25345023_2.fastq.gz | Fastqsanger.gz | |||
| SRR25345024_1.fastq.gz | Fastqsanger.gz |
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Project description:RNA N6-methyladenosine (m6A) modification is present in different RNA molecules, including protein-coding mRNAs and non-coding RNAs such as ribosomal RNAs (rRNAs).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.
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Project description:N6-methyladenosine (m6A) has recently been found abundantly on messenger RNA and shown to regulate most steps of mRNA metabolism. Several important m6A methyltransferases have been described functionally and structurally, but the enzymes responsible for installing one m6A residue on each subunit of human ribosomes at functionally important sites have eluded identification for over 30 years. Here we identify METTL5 as the enzyme responsible for 18S rRNA m6A modification and confirm ZCCHC4 as the 28S rRNA modification enzyme. We show that METTL5 must form a heterodimeric complex with TRMT112, a known methyltransferase activator, to gain metabolic stability in cells. We provide the first atomic resolution structure of METTL5-TRMT112, supporting that its RNA binding mode differs distinctly from that of other m6A RNA methyltransferases. On the basis of similarities with a DNA methyltransferase, we propose that METTL5-TRMT112 acts by extruding the adenosine to be modified from a double-stranded nucleic acid.
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Project description:Defects in ribosome biogenesis can trigger a battery of cellular events to alter gene expression and cell growth. 18S rRNA methyltransferase EMG1 is an important assembly factor in ribosome biogenesis. Here, we report that downregulation of EMG1 non-enzymatically leads to decreased N6-methyladensine (m6A) levels in polyadenylated RNA. We revealed the identities of the messenger RNAs with decreased m6A intensities upon EMG1 deficiency using m6A-IP-seq. This group of mRNAs significantly overlap with the CLIP targets of IGF2BP3, which is an m6A reader protein stabilizing m6A-containing transcripts. Furthermore, both RNA-seq and qRT-PCR results suggest that the expression level of this group of mRNAs significantly decreased upon EMG1 deficiency, possibly through the regulation of IGF2BP3. Gene ontology analysis suggests that this group of mRNAs function in a list of cell signaling pathways important for cell growth. These findings collectively suggest that decreased ribosome assembly may influence gene expression via decreasing m6A levels in mRNAs.
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Project description:18S rRNA methyltransferase EMG1 non-enzymatically influence m6A in mRNA
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Project description:Identifying processes occurring in early life affect subsequent life and health span is an urgent aim to improve human health. In this study, we identified a novel mechanism of dFOXO in longevity determination in Drosophila. We found that early adulthood induction of dFOXO is sufficient to reduce mortality in old age through different pathways than chronic dFOXO. We showed that dFOXO requires specific ATP-dependent chromatin modifiers to extend lifespan, and we could mimic this lifespan extension by modulating dFOXO’s targets in later life. Furthermore, dFOXO in early life induces a specific transcriptional programme that counteracts the natural transcriptomic changes occurring with age. Our findings provide a better understanding of transcriptional mechanisms related to longevity and opens new avenues for possible time-restricted interventions to improve human health in the future.
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Project description:Cellular RNAs are covalently modified and these modifications can impact on all biological processes and hence are implicated in different types of diseases. Amongst RNA modifications, N6-methyladenosine (m6A) is one of the most widespread and has been found on messenger (mRNA), ribosomal (rRNA), non-coding and spliceosomal RNAs. We undertook a systematic screen to uncover new RNA-methyltransferases. We demonstrate that the methyltransferase-like 5 protein (METTL5) is an 18S rRNA specific methyltransferase and interacts specifically with Trmt122.
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Project description:Tumor recurrence is main pattern of treatment failure for early-stage hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying disease recurrence remain poorly understood. Here, we showed that 18S rRNA N6-methyladenosine (m6A1832) modification and its methyltransferase complex METTL5/TRMT112 were upregulated in HCC and correlated with poor prognosis. Loss-of-function and gain-of-function assays demonstrated that METTL5/TRMT112 mediated 18S rRNA m6A1832 modification promotes HCC tumorigenesis in vitro and in vivo. Mechanistically, 18S rRNA m6A1832 modification selectively regulated the translation of mRNAs with long 5’UTR and short 3’UTR through affecting the assembly of 80S subunit at translation initiation and its dissociation at translation termination which was executed by weakening the interaction of ABCE1 with eRF1 and eRF3. Moreover, METTL5-mediated 18S rRNA m6A1832 modification regulated β-oxidation of long-chain fatty acid through ACSL4 to promote HCC progression. Our work uncovered a novel layer of mRNA translation regulation mechanism at ribosome 80S subunit assembly and dissociation step mediated by 18S rRNA m6A1832 modification and revealed a new crosslink between RNA epigenetic modification and fatty acid metabolism in HCC.
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