International Journal of Oral Science
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2024
·Vol. 16
·期 1
·1-13
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IF 10.8
Li Shujin,Feng Tian,Liu Yuantong,Yang Qichao,Song An,Wang Shuo,Xie Jun,Zhang Junjie,Yuan Bifeng,Sun Zhijun
N 1 -methyladenosine (m 1 A) RNA methylation is critical for regulating mRNA translation; however, its role in the development, progression, and immunotherapy response of head and neck squamous cell carcinoma (HNSCC) remains largely unknown. Using Tgfbr1 and Pten conditional knockout (2cKO) mice, we found the neoplastic transformation of oral mucosa was accompanied by increased m 1 A modification levels. Analysis of m 1 A-associated genes identified TRMT61A as a key m 1 A writer linked to cancer progression and poor prognosis. Mechanistically, TRMT61A-mediated tRNA-m 1 A modification promotes MYC protein synthesis, upregulating programmed death-ligand 1 (PD-L1) expression. Moreover, m 1 A modification levels were also elevated in tumors treated with oncolytic herpes simplex virus (oHSV), contributing to reactive PD-L1 upregulation. Therapeutic m 1 A inhibition sustained oHSV-induced antitumor immunity and reduced tumor growth, representing a promising strategy to alleviate resistance. These findings indicate that m 1 A inhibition can prevent immune escape after oHSV therapy by reducing PD-L1 expression, providing a mutually reinforcing combination immunotherapy approach.
研究领域:
肿瘤学
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免疫学
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分子生物学
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癌症治疗
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PubMed
高影响因子
DEVELOPMENTAL CELL
·
2024
·
IF 10.7
Rongrong He,Ziwei Lv,Yinan Li,Shuchao Ren,Jiaqi Cao,Jun Zhu,Xinrong Zhang,Huimin Wu,Lihao Wan,Ji Tang,Shutong Xu,Xiao-Lin Chen,Zhipeng Zhou
Ergosterols are essential components of fungal plasma membranes. Inhibitors targeting ergosterol biosynthesis (ERG) genes are critical for controlling fungal pathogens, including Magnaporthe oryzae , the fungus that causes rice blast. However, the translational mechanisms governing ERG gene expression remain largely unexplored. Here, we show that the Trm6/Trm61 complex catalyzes dynamic N 1 -methyladenosine at position 58 (m 1 A58) in 51 transfer RNAs (tRNAs) of M. oryzae , significantly influencing translation at both the initiation and elongation stages. Notably, tRNA m 1 A58 promotes elongation speed at most cognate codons mainly by enhancing eEF1-tRNA binding rather than affecting tRNA abundance or charging. The absence of m 1 A58 leads to substantial decreases in the translation of ERG genes, ergosterol production, and, consequently, fungal virulence. Simultaneously targeting the Trm6/Trm61 complex and the ergosterol biosynthesis pathway markedly improves rice blast control. Our findings demonstrate an important role of m 1 A58-mediated translational regulation in ergosterol production and fungal infection, offering a potential strategy for fungicide development.
研究领域:
分子生物学
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微生物学
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植物病理学
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PubMed
高影响因子
Advanced Science
·
2026
·
IF 14.1
Yueyang Li,Sifei Yu,Kaidong Lu,Yujie Zhang,Mingjie Dong,Yan Peng,Liang Xue,Waleed Alam,Yuxuan Shui,Yi Zhou,Wuyunhan Ma,Meng Bao,Peiming Li,Peiyi Luo,Tiezhan Lu,Jiajia Li,Kang Zhang,Yuying Wang,Shuchen Yang,Nuoya Yin,Francesco Faiola,Zilong Gao,Jingfeng Zhou,Fei Zhao,Yali He,Magdalena J. Koziol
Amyloid-beta (Aβ) aggregation, mitochondrial dysfunction, and cognitive decline are hallmarks of Alzheimer's disease (AD), but its initiating molecular events remain unknown. Given that RNA modifications regulate neurodevelopment and neurodegeneration, we explore their functional role in 5xFAD mice, an Aβ AD model. We discover that N1-methyladenosine (m1A) is the most altered RNA modification, and that its regulator demethylase, ALKBH3 is upregulated. Strikingly, Alkbh3 reduction decreases Aβ plaques and restores cognition. Conversely, elevated ALKBH3 levels, observed in AD patients, compromise neuronal morphology and mitochondrial function by impairing mitophagy (degradation of dysfunctional mitochondria), a known driver of neuronal dysfunction. Mechanistically, we reveal that ALKBH3 removes m1A from PINK1 mRNA, the mitophagy master regulator. Given that ALKBH3 is elevated in human AD, causally linked to mitophagy impairment, and confers neuroprotection when depleted, we present ALKBH3 as a mechanistically validated therapeutic target in AD.
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高影响因子
CELLULAR & MOLECULAR BIOLOGY LETTERS
·
2026
·Vol. 31
·期 1
·33
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IF 12.2
Ding Ying,Feng Ziyang,Chen Guanjun,Liu Yunqing,Zhu Yuxing,Cao Ke
Background Anaplastic thyroid cancer (ATC) is a highly aggressive malignancy with rapid progression and poor prognosis. Although N1-methyladenosine (m 1 A) modification has been implicated in cancer development, the specific role of tRNA m 1 A modification in ATC remains unclear. Methods An integrated multi-omics approach is employed, including m 1 A-MAP-tRNA-seq, tRNA-seq, RNA-seq, and Ribo-seq, complemented by functional assays such as tRNA aminoacylation assay, puromycin intake assay, and L-HPG staining. Additional experiments involved polysome profiling qRT-PCR, codon-switch assay, endoplasmic reticulum (ER)-tracker and TPE-MI staining, transmission electron microscopy, ChIP-qPCR, dual-luciferase reporter assay, and BODIPY staining to elucidate the underlying mechanism. Results TRMT6/TRMT61A is significantly upregulated in ATC. The complex promotes tumor cell proliferation and metastasis by enhancing the aminoacylation of specific tRNAs, thereby facilitating global protein translation. Elevated translation led to the accumulation of unfolded proteins in the ER, which activates the IRE1α–XBP1s pathway. Notably, m 1 A modification also increased IRE1α translation, further amplifying the pathway. Activation of the IRE1α–XBP1s pathway upregulates DGAT1 expression, which promotes triglyceride synthesis. Conclusions Together, these findings reveal a previously unrecognized mechanism by which TRMT6/TRMT61A drives ATC progression through translational and metabolic reprogramming, identifying TRMT6/TRMT61A as a promising therapeutic target in ATC. Graphical abstract
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高影响因子
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