A human tRNA methyltransferase 9‐like protein prevents tumour growth by regulating LIN9 and HIF1‐α

Begley, Ulrike; Sosa, María Soledad; Avivar-Valderas, Álvaro; Patil, Ashish; Endres, Lauren; Estrada, Yeriel; Chan, Ching-Kit; Su, Dan; Dedon, Peter C.; Aguirre‐Ghiso, Julio A.; Begley, Thomas J.

doi:10.1002/emmm.201201161

Cited by 100 publications

(118 citation statements)

References 43 publications

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“…Similarly, the methyltransferase NSUN2 has been found to be overexpressed in breast cancer and its expression levels have been shown to correlate with cancer development and progression . In contrast, the tRNA methyltransferase TRM9L/KIAA1456 has been found to be down-regulated in breast cancer cells, as well as in other forms of cancer (Begley et al 2013). Lastly, TRMT12 was found to be overexpressed in 87% of breast tumors (Rodriguez et al 2007).…”

Section: Wwwrnajournalorg 1759mentioning

confidence: 99%

“…More recent approaches have used liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodologies, which can provide accurate quantitation of multiple RNA modifications across conditions and cell types (Chan et al 2010;Addepalli and Limbach 2011;Yan et al 2013;Su et al 2014) and have been successfully applied to a wide variety of species (Chan et al 2010;Patil et al 2012;Begley et al 2013). Selective enzymatic digestions of individual RNAs with a battery of RNases, coupled to LC-MS/MS techniques, has been shown to be extremely useful for comparative RNA modification analysis across species and conditions (Li and Limbach 2012).…”

Section: Detecting Rna Modifications: Past Present and Future Effortsmentioning

confidence: 99%

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The RNA modification landscape in human disease

Jonkhout

Tran

Smith

et al. 2017

RNA

434

366

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RNA modifications have been historically considered as fine-tuning chemo-structural features of infrastructural RNAs, such as rRNAs, tRNAs, and snoRNAs. This view has changed dramatically in recent years, to a large extent as a result of systematic efforts to map and quantify various RNA modifications in a transcriptome-wide manner, revealing that RNA modifications are reversible, dynamically regulated, far more widespread than originally thought, and involved in major biological processes, including cell differentiation, sex determination, and stress responses. Here we summarize the state of knowledge and provide a catalog of RNA modifications and their links to neurological disorders, cancers, and other diseases. With the advent of direct RNA-sequencing technologies, we expect that this catalog will help prioritize those RNA modifications for transcriptome-wide maps.

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Section: Wwwrnajournalorg 1759mentioning

confidence: 99%

Section: Detecting Rna Modifications: Past Present and Future Effortsmentioning

confidence: 99%

The RNA modification landscape in human disease

Jonkhout

Tran

Smith

et al. 2017

RNA

434

366

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“…However, hTRM9L is silenced in colon cancer models, and over expression of hTRM9L expression in colorectal cancer cells prevents tumor growth. 22 Putting these data together, Dr. Begley presented a model whereby ALKBH8 and hTRM9L may work together to control ROS, DNA damage, and tumor growth. ALKBH8 turns on translation of the selenocysteine-containing proteins needed for ROS detoxification and DNA repair, while hTRM9L may prevent their translation or lead to their degradation by an unknown mechanism.…”

Section: Epitranscriptomicsmentioning

confidence: 99%

RNA editing, epitranscriptomics, and processing in cancer progression

Witkin

Hanlon

Strasburger

et al. 2014

Cancer Biology & Therapy

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The transcriptome is extensively and dynamically regulated by a network of RNA modifying factors. RNA editing enzymes APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) and ADAR (adenosine deaminase, RNA-specific) irreversibly recode primary RNA sequences, whereas newly described methylases (writers) and demethylases (erasers) dynamically alter RNA molecules in response to environmental conditions. RNA modifications can affect RNA splicing, nuclear-cytoplasmic transport, translation, and regulation of gene expression by RNA interference. In addition, tRNA base modifications, processing, and regulated cleavage have been shown to alter global patterns of mRNA translation in response to cellular stress pathways. Recent studies, some of which were discussed at this workshop, have rekindled interest in the emerging roles of RNA modifications in health and disease. On September 10th, 2014, the Division of Cancer Biology, NCI sponsored a workshop to explore the role of epitranscriptomic RNA modifications and tRNA processing in cancer progression. The workshop attendees spanned a scientific range including chemists, virologists, and RNA and cancer biologists. The goal of the workshop was to explore the interrelationships between RNA editing, epitranscriptomics, and RNA processing and the enzymatic pathways that regulate these activities in cancer initiation and progression. At the conclusion of the workshop, a general discussion focused on defining the major challenges and opportunities in this field, as well as identifying the tools, technologies, resources and community efforts required to accelerate research in this emerging area.

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“…Altered levels of tRNA modification have been linked to several disorders including cancers (2)(3)(4)(5)(6)(7)(8). One of the most common modified nucleosides, dihydrouridine, is produced by reduction of the C5-C6 double bond in uridine.…”

mentioning

confidence: 99%

Major reorientation of tRNA substrates defines specificity of dihydrouridine synthases

Byrne

Jenkins

Peters

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The reduction of specific uridines to dihydrouridine is one of the most common modifications in tRNA. Increased levels of the dihydrouridine modification are associated with cancer. Dihydrouridine synthases (Dus) from different subfamilies selectively reduce distinct uridines, located at spatially unique positions of folded tRNA, into dihydrouridine. Because the catalytic center of all Dus enzymes is conserved, it is unclear how the same protein fold can be reprogrammed to ensure that nucleotides exposed at spatially distinct faces of tRNA can be accommodated in the same active site. We show that the Escherichia coli DusC is specific toward U16 of tRNA. Unexpectedly, crystal structures of DusC complexes with tRNA Phe and tRNATrp show that Dus subfamilies that selectively modify U16 or U20 in tRNA adopt identical folds but bind their respective tRNA substrates in an almost reverse orientation that differs by a 160°rotation. The tRNA docking orientation appears to be guided by subfamily-specific clusters of amino acids ("binding signatures") together with differences in the shape of the positively charged tRNA-binding surfaces. tRNA orientations are further constrained by positional differences between the C-terminal "recognition" domains. The exquisite substrate specificity of Dus enzymes is therefore controlled by a relatively simple mechanism involving major reorientation of the whole tRNA molecule. Such reprogramming of the enzymatic specificity appears to be a unique evolutionary solution for altering tRNA recognition by the same protein fold.dihydrouridine synthase | tRNA modification | protein-RNA interaction | substrate specificity | X-ray crystallography D uring the posttranscriptional maturation of tRNA, about 10% of its nucleosides are enzymatically modified at specific positions (1). Altered levels of tRNA modification have been linked to several disorders including cancers (2-8). One of the most common modified nucleosides, dihydrouridine, is produced by reduction of the C5-C6 double bond in uridine. The resulting nonplanar base cannot form stabilizing stacking interactions with neighboring nucleotides and favors the C2′-endo ribose conformation (9). In Escherichia coli, dihydrouridine is commonly found at positions 16, 17, 20, and 20a of the D loop of tRNA (Fig. S1A). The formation of dihydrouridine is catalyzed by dihydrouridine synthases (Dus) (10-12). Different Dus subfamilies display specificity toward distinct subsets of target uridines in tRNA. Whereas the specificity of the four Saccharomyces cerevisiae Dus enzymes has been established (13), little is known about the three E. coli Dus proteins (DusA, DusB, and DusC), except that the specificities are nonoverlapping and that DusA modifies U20 (10). The mechanistic basis of the exquisite substrate specificity of Dus is an intriguing problem because the target uridines are exposed at spatially distinct faces of folded tRNAs, and yet all Dus subfamilies are predicted to adopt the same fold with highly conserved active-site residues (14-16).A stru...

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A human tRNA methyltransferase 9‐like protein prevents tumour growth by regulating LIN9 and HIF1‐α

Cited by 100 publications

References 43 publications

The RNA modification landscape in human disease

The RNA modification landscape in human disease

RNA editing, epitranscriptomics, and processing in cancer progression

Major reorientation of tRNA substrates defines specificity of dihydrouridine synthases

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