The emerging impact of tRNA modifications in the brain and nervous system

Ramos, Jillian; Fu, Dragony

doi:10.1016/j.bbagrm.2018.11.007

Cited by 54 publications

(44 citation statements)

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“…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). In particular, the brain appears to be sensitive to any perturbation in translation efficiency and fidelity brought about by defects in tRNA modifications, as evidenced from the numerous cognitive disorders linked to tRNA modification enzymes such as: the Elongator complex (Hawer et al, 2018; Kojic & Wainwright, 2016); ADAT3 (Alazami et al, 2013; El‐Hattab et al, 2016; Ramos, Han, et al, 2019); NSUN2 (Abbasi‐Moheb et al, 2012; Khan et al, 2012; Martinez et al, 2012); FTSJ1 (Dai et al, 2008; Freude et al, 2004; Froyen et al, 2007; Gong et al, 2008; Guy et al, 2015; Ramser et al, 2004; Takano et al, 2008); WDR4 (Chen et al, 2018; Shaheen et al, 2015; Trimouille et al, 2018); KEOPS complex (Braun et al, 2017); PUS3 (Abdelrahman, Al‐Shamsi, Ali, & Al‐Gazali, 2018; Shaheen, Han, et al, 2016); CTU2 (Shaheen, Al‐Salam, El‐Hattab, & Alkuraya, 2016; Shaheen, Mark, et al, 2019); TRMT10A (Gillis et al, 2014; Igoillo‐Esteve et al, 2013; Narayanan et al, 2015; Yew, McCreight, Colclough, Ellard, & Pearson, 2016; Zung et al, 2015); PUS7 (de Brouwer et al, 2018; Shaheen, Tasak, et al, 2019); and ALKBH8 (Monies, Vagbo, Al‐Owain, Alhomaidi, & Alkuraya, 2019).…”

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

et al. 2020

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“…20 Furthermore, the complete maturation of certain tRNAs needs the removal of introns between positions 37 and 38. 23,24 Upon completion of processing, the mature tRNAs are charged with their cognate amino acids by aminoacyl-tRNA synthetases (aaRSs) to participate in protein synthesis. 21,22 Meanwhile, in order to ensure their stability, proper folding and function, it is necessary to specifically modify the tRNA nucleotides, especially in the anticodon stem loop.…”

Section: Structure Of Trnasmentioning

confidence: 99%

“…21,22 Meanwhile, in order to ensure their stability, proper folding and function, it is necessary to specifically modify the tRNA nucleotides, especially in the anticodon stem loop. 23,24 Upon completion of processing, the mature tRNAs are charged with their cognate amino acids by aminoacyl-tRNA synthetases (aaRSs) to participate in protein synthesis. In addition, tRNAs are a source of a class of small RNAs known as tRNA derivatives, such as tRNA-derived small RNAs (tsR-NAs), 25 tRNA-derived fragments (tRFs), 26 i-tRFs 27,28 and tRNA-derived stress-induced RNAs (tiRNAs).…”

Section: Structure Of Trnasmentioning

confidence: 99%

The tRNA‐associated dysregulation in immune responses and immune diseases

et al. 2019

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Transfer RNA (tRNA), often considered as a housekeeping molecule, mainly participates in protein translation by transporting amino acids to the ribosome. Nevertheless, accumulating evidence has shown that tRNAs are closely related to various physiological and pathological processes. The proper functioning of the immune system is the key to human health. The aim of this review is to investigate the relationships between tRNAs and the immune system. We detail the biogenesis and structure of tRNAs and summarize the pathogen tRNA-mediated infection and host responses. In addition, we address recent advances in different aspects of tRNA-associated dysregulation in immune responses and immune diseases, such as tRNA molecules, tRNA modifications, tRNA derivatives and tRNA aminoacylation. Therefore, tRNAs play an important role in immune regulation. Although our knowledge of tRNAs in the context of immunity remains, for the most part, unknown, this field deserves in-depth research to provide new ideas for the treatment of immune diseases. K E Y W O R D Sbiogenesis, immune diseases, immune responses, tRNA F I G U R E 1 The biogenesis and structure of tRNAs. tRNA: Transfer RNA; Pol III: RNA polymerase III; pre-tRNA: Precursor tRNA; mRNA: Messenger RNA; aaRS: Aminoacyl-tRNA synthetase; tsRNA: tRNA-derived small RNA; tRF: tRNA-derived fragment; tiRNA: tRNA-derived stress-induced RNA

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“…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). In particular, the brain appears to be exquisitely sensitive to any perturbation in translation efficiency and fidelity brought about by defects in tRNA modifications, as evidenced from the numerous cognitive disorders linked to tRNA modification (Abbasi-Moheb et al 2012;Alazami et al 2013;Blanco et al 2014;de Brouwer et al 2018;El-Hattab et al 2016;Khan et al 2012;Komara et al 2015;Martinez et al 2012;Monies et al 2019;Ramos et al 2019;Shaheen et al 2015;Shaheen et al 2016a;Shaheen et al 2016b;Shaheen et al 2019a;Shaheen et al 2019b).…”

Section: Introductionmentioning

confidence: 99%

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

Zhang

Lentini

Prevost

et al. 2019

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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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The emerging impact of tRNA modifications in the brain and nervous system

Cited by 54 publications

References 286 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

The tRNA‐associated dysregulation in immune responses and immune diseases

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

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