METTL8

Last update 08 May 2025

Basic Info

Synonyms

FLJ13984, methyltransferase 8, methylcytidine, Methyltransferase-like protein 8

+ [4]

Introduction

Mitochondrial S-adenosyl-L-methionine-dependent methyltransferase that mediates N(3)-methylcytidine modification of residue 32 of the tRNA anticodon loop of mitochondrial tRNA(Ser)(UCN) and tRNA(Thr) (PubMed:34774131, PubMed:35017528). N(3)-methylcytidine methylation modification regulates mitochondrial translation efficiency and is required for activity of the respiratory chain (PubMed:34774131, PubMed:35017528). N(3)-methylcytidine methylation of mitochondrial tRNA(Ser)(UCN) requires the formation of N(6)-dimethylallyladenosine(37) (i6A37) by TRIT1 as prerequisite (PubMed:34774131, PubMed:35017528). May also mediate N(3)-methylcytidine modification of mRNAs (PubMed:28655767). The existence of N(3)-methylcytidine modification on mRNAs is however unclear, and additional evidences are required to confirm the role of the N(3)-methylcytidine-specific mRNA methyltransferase activity of METTL8 in vivo (PubMed:33313824, PubMed:34774131).

100 Clinical Results associated with METTL8

100 Translational Medicine associated with METTL8

0 Patents (Medical) associated with METTL8

Literatures (Medical) associated with METTL8

01 Mar 2025·Molecular Neurobiology

Identification of Potential Causal Genes for Neurodegenerative Diseases by Mitochondria-Related Genome-Wide Mendelian Randomization

Article

Author: Chi, Li-Yi ; Li, Ju-Rong ; Gu, Xiao-Jing ; Chen, Ting ; Yin, Kang-Fu ; Su, Wei-Ming ; Wen, Xiang-Jin ; Chen, Yong-Ping ; Jiang, Zheng ; Duan, Qing-Qing ; Cao, Bei

Current research lacks comprehensive investigations into the potential causal link between mitochondrial-related genes and the risk of neurodegenerative diseases (NDDs). We aimed to identify potential causative genes for five NDDs through an examination of mitochondrial-related gene expression levels. Through the integration of summary statistics from expression quantitative trait loci (eQTL) datasets (human blood and brain tissue), mitochondrial DNA copy number (mtDNA-CN), and genome-wide association studies (GWAS) datasets of five NDDs from European ancestry, we conducted a Mendelian randomization (MR) analysis to explore the potential causal relationship between mitochondrial-related genes and Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Lewy body dementia (LBD). Sensitivity analysis and Bayesian colocalization were employed to validate this causal relationship. Through MR analysis, we have identified potential causal relationships between 12 mitochondria-related genes and AD, PD, ALS, and FTD overlapping with motor neuron disease (FTD_MND) in human blood or brain tissue. Bayesian colocalization analysis further confirms 9 causal genes, including NDUFS2, EARS2, and MRPL41 for AD; NDUFAF2, MALSU1, and METTL8 for PD; MYO19 and MRM1 for ALS; and FASTKD1 for FTD_MND. Importantly, in both human blood and brain tissue, NDUFS2 exhibits a significant pathogenic effect on AD, while NDUFAF2 demonstrates a robust protective effect on PD. Additionally, the mtDNA-CN plays a protected role in LBD (OR = 0.62, p = 0.031). This study presents evidence establishing a causal relationship between mitochondrial dysfunction and NDDs. Furthermore, the identified candidate genes may serve as potential targets for drug development aimed at preventing NDDs.

27 Feb 2025·Nucleic Acids Research

Transcriptome-wide mapping of N3-methylcytidine modification at single-base resolution

Article

Author: Sheng, Jia ; Wei, Saisai ; Yan, Sujun ; Gao, Yunyi ; Gao, Xiangwei ; Zhang, Jun ; Hou, Jingyu ; Chen, Zhanghui ; Wu, Canlan

Abstract3-Methylcytidine (m3C), a prevalent modification of transfer RNAs (tRNAs), was recently identified in eukaryotic messenger RNAs (mRNAs). However, its precise distribution and formation mechanisms in mRNAs remain elusive. Here, we develop a novel approach, m3C immunoprecipitation and sequencing (m3C-IP-seq), utilizing antibody enrichment to profile the m3C methylome at single-nucleotide resolution. m3C-IP-seq captures 12 cytoplasmic tRNA isoacceptors and 2 mitochondrial tRNA isoacceptors containing m3C modifications. Moreover, m3C-IP-seq permits the comprehensive profiling of m3C sites in mRNAs and long noncoding RNAs, with their presence reliant on a nuclear isoform of METTL8. A significant proportion of m3C sites is concentrated in the 3′ untranslated region (3′ UTR) of mRNAs and is associated with mRNA degradation. Additionally, m3C methylation is dynamic and responds to hypoxia. Collectively, our data demonstrate the widespread presence of m3C modification in the human transcriptome and provide a resource for functional studies of m3C-mediated RNA metabolism.

01 Jan 2025·Experimental Cell Research

Targeting METTL8 with Rabdosiin overcomes lenvatinib resistance in hepatocellular carcinoma

Article

Author: Zhang, Hong-Mei ; Yu, Pengfei ; Zhang, Kuo ; Liu, Yunpeng ; Zhang, Wangqian ; Gao, Yuan ; Wang, Shuning ; Han, Xiao ; Wang, Xiang-Xu ; Chen, Muhua ; Liu, Lei ; Lei, Xiaoying

In hepatocellular carcinoma (HCC), lenvatinib is a key first-line treatment that significantly improves survival in some patients with advanced stage. However, lenvatinib resistance presents a major clinical challenge. This study aims to identify key molecular factors driving lenvatinib resistance in HCC and propose intervention strategies to overcome this resistance, thereby enhancing therapeutic efficacy. A genome-wide CRISPR-Cas9 activation screen identified METTL8 as a crucial gene associated with lenvatinib resistance. Validation through in vitro and in vivo assays confirmed METTL8's role in mediating lenvatinib resistance. Higher METTL8 expression was observed in lenvatinib-resistant HCC cells compared to parental cells. Immunohistochemical staining of tissue sections from HCC patients revealed a negative correlation between high METTL8 expression and lenvatinib sensitivity. To inhibit the function of METTL8 that mediate lenvatinib resistance, we conducted a screening using a natural compound library, virtual drug screening identified Rabdosiin as a potential METTL8 inhibitor, subsequent experiments demonstrated that Rabdosiin could effectively overcome METTL8-mediated lenvatinib resistance. In conclusion, this research highlights METTL8 as a novel target for mitigating lenvatinib resistance, proposing that targeting METTL8 could restore lenvatinib sensitivity in HCC, and underscores its value as a biomarker for lenvatinib application in clinical settings.

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