The chemical diversity of RNA modifications

Ontiveros, Robert Jordan; Stoute, Julian; Liu, Kathy Fange

doi:10.1042/bcj20180445

Cited by 120 publications

(110 citation statements)

References 189 publications

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“…The posttranscriptional modification of transfer RNA (tRNA) has emerged as a critical modulator of biological processes ranging from gene expression to development (Frye, Harada, Behm, & He, 2018; Ranjan & Leidel, 2019). There are over 100 types of tRNA modifications that range from simple methylation to complex modifications involving multiple chemical groups (El Yacoubi, Bailly, & de Crecy‐Lagard, 2012; Ontiveros, Stoute, & Liu, 2019). Notably, defects in tRNA modification have emerged as the cause of diverse neurological and neurodevelopmental disorders, thereby highlighting the critical role of tRNA modification in human health and physiology (Angelova et al, 2018; Ramos & Fu, 2019).…”

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confidence: 99%

An intellectual disability‐associated missense variant in TRMT1 impairs tRNA modification and reconstitution of enzymatic activity

et al. 2020

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The human TRMT1 gene encodes an RNA methyltransferase enzyme responsible for catalyzing dimethylguanosine (m2,2G) formation in transfer RNAs (tRNAs). Frameshift mutations in TRMT1 have been shown to cause autosomal-recessive intellectual disability (ID) in the human population but additional TRMT1 variants remain to be characterized. Here, we describe a homozygous TRMT1 missense variant in a patient displaying developmental delay, ID, and epilepsy. The missense variant changes an arginine residue to a cysteine (R323C) within the methyltransferase domain and is expected to perturb protein folding. Patient cells expressing TRMT1-R323C exhibit a deficiency in m2,2G modifications within tRNAs, indicating that the mutation causes loss of function. Notably, the TRMT1 R323C mutant retains tRNA binding but is unable to rescue m2,2G formation in TRMT1-deficient human cells. Our results identify a pathogenic point mutation in TRMT1 that perturbs tRNA modification activity and demonstrate that m2,2G modifications are disrupted in the cells of patients with TRMT1-associated ID disorders.

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confidence: 99%

An intellectual disability‐associated missense variant in TRMT1 impairs tRNA modification and reconstitution of enzymatic activity

et al. 2020

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“…The post-transcriptional modification of tRNA has emerged as a critical modulator of biological processes ranging from gene expression to development (Frye et al 2018;Ranjan and Leidel 2019). There are over 100 types of tRNA modifications that range from simple methylation to complex modifications involving multiple chemical groups (El Yacoubi et al 2012;Ontiveros et al 2019). Notably, defects in tRNA modification have emerged as the cause of diverse neurological and neurodevelopmental disorders, thereby highlighting the critical role of tRNA modification in human health and physiology (Angelova et al 2018;Ramos and Fu 2018).…”

Section: Introductionmentioning

confidence: 99%

A missense variant impairing TRMT1 function in tRNA modification is linked to intellectual disability

Zhang

Lentini

Prevost

et al. 2019

Preprint

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The human TRMT1 gene encodes a tRNA methyltransferase enzyme responsible for the formation of the dimethylguanosine (m2,2G) modification in cytoplasmic and mitochondrial tRNAs. Frameshift mutations in the TRMT1 gene have been shown to cause autosomal-recessive intellectual disability (ID) in the human population but additional TRMT1 variants remain to be characterized. Moreover, the impact of ID-associated TRMT1 mutations on m2,2G levels in IDaffected patients is unknown. Here, we describe a homozygous missense variant in TRMT1 in a patient displaying developmental delay, ID, and epilepsy. The missense variant changes a conserved arginine residue to a cysteine (R323C) within the methyltransferase domain of TRMT1 and is expected to perturb protein folding. Patient cells expressing the TRMT1-R323C variant exhibit a severe deficiency in m2,2G modifications within tRNAs, indicating that the mutation causes loss-of-function. Notably, the TRMT1 R323C mutant retains the ability to bind tRNA but is unable to rescue m2,2G formation in TRMT1-deficient human cells. Our results identify a pathogenic point mutation in TRMT1 that severely perturbs tRNA modification activity, and provide the first demonstration that m2,2G modifications are disrupted in patients with TRMT1associated ID disorders.

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“…Currently, around 150-170 RNA modifications are known, and recent reports show that RNA modifications play an important role in tRFs cleavage in different organisms. Indeed, tRNA is the most extensively modified RNA in a cell (up to 25% of nucleotides per tRNA) (Delaunay and Frye, 2019;Jordan Ontiveros et al, 2019). Epitranscriptomics has recently emerged as a new field to comprehend the mechanisms underlying RNA modifications and their role in gene expression.…”

Section: Introductionmentioning

confidence: 99%

“…2'-O-methylation is one of the most common RNA modifications and consists in the addition of a methyl group to the 2' hydroxyl of the ribose moiety of a nucleoside, being also known as Nm. It is found in tRNAs, rRNAs, snRNAs (small nuclear RNAs) at the 3' end of some small non-coding RNAs (such as piRNAs) and at some sites on mRNAs (Jordan Ontiveros et al, 2019). This modification plays a wide range of roles in RNA structure, stability and interactions (Dimitrova et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

tRNA fragments (tRFs) populations analysis in mutants affecting tRNAs processing and tRNA methylation

Mollà-Herman¹,

Angelova²,

Carré³

et al. 2019

Preprint

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tRNA fragments (tRFs) are a class of small non-coding RNAs (sncRNAs) derived from tRNAs. tRFs are highly abundant in many cell types including stem cells and cancer cells, and are found in all domains of life. Beyond translation control, tRFs have several functions ranging from transposon silencing to cell proliferation control. However, the analysis of tRFs presents specific challenges and their biogenesis is not well understood. They are very heterogeneous and highly modified by numerous post-transcriptional modifications. Here we describe a bioinformatic pipeline to study tRFs populations and shed light onto tRNA fragments biogenesis. Indeed, we used small RNAs Illumina sequencing datasets extracted from wild type and mutant Drosophila ovaries affecting two different highly conserved steps of tRNA biogenesis: 5'pre-tRNA processing (RNase-P subunit Rpp30) and tRNA 2'-O-methylation (CG7009 and CG5220). Using our pipeline, we show how defects in tRNA biogenesis affect nuclear and mitochondrial tRFs populations and other small non-coding RNAs biogenesis, such as small nucleolar RNAs (snoRNAs). This tRF analysis workflow will advance the current understanding of tRFs biogenesis, which is crucial to better comprehend tRFs roles and their implication in human pathology. MATERIALS AND METHODS Fly stocksFly stocks are described in (Molla-Herman et al., 2015;M. Angelova, 2019). RNA extraction from ovariesRNA was extracted from Drosophila ovaries following standard methods detailed in (Molla-Herman et al., 2015;M. Angelova, 2019). Small RNA sequencingRNA samples of 3-5 µg were used for High-throughput sequencing using Illumina HiSeq, 10% single-reads lane 1×50 bp. (Fasteris). 15-29 nt RNAs sequences excluding rRNA (riboZero) were sequenced. All the analyses were performed with Galaxy tools https://mississippi.snv.jussieu.fr. Data set deposition is described in (Molla-Herman et al., 2015;M. Angelova, 2019). European Nucleotide Archive (ENA) of the EMBL-EBI (http://www.ebi.ac.uk/ena), accession numbers: PRJEB10569 (Rpp30 mutants), PRJEB35301 and PRJEB35713 (Nm mutants). Clipping and concatenationRaw data were used for clipping the adaptors [Clip adapter (Galaxy-Version 2.3.0, owner: artbio)] and FASTQ quality control was performed (FastQC Read Quality reports (Galaxy-Version 0.72)). Since replicates were homogeneous in quality and analysis (replicates for CG7009* heterozygous and homozygous, triplicates for CG7009*-CG5220* double mutants) we merged them [Concatenate multiple datasets tailto-head (Galaxy-Version 1.4.1, owner: artbio) to have single fasta files. CG7009*/Def9487 was used to obtain normalization numbers but is not shown in the figures. Data normalization using DeSeq miRNA countsData were normalized with bank Size Factors (SF) obtained by using [DESeq geometrical normalization (Galaxy-Version 1.0.1, owner: artbio)] with miRNA counts obtained using [miRcounts (Galaxy-Version 1.3.2)], allowing 0 mismatch (MM). Then, 1/SF values were used in Galaxy small RNA maps (Sup. Fig. 5). Data normalization with DeSeq using ...

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The chemical diversity of RNA modifications

Cited by 120 publications

References 189 publications

An intellectual disability‐associated missense variant in TRMT1 impairs tRNA modification and reconstitution of enzymatic activity

An intellectual disability‐associated missense variant in TRMT1 impairs tRNA modification and reconstitution of enzymatic activity

A missense variant impairing TRMT1 function in tRNA modification is linked to intellectual disability

tRNA fragments (tRFs) populations analysis in mutants affecting tRNAs processing and tRNA methylation

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