NSUN6, or Nop2/Sun RNA methyltransferase family member 6, is a methyltransferase that specifically targets mRNA. It mainly methylates cytosine-5 in the three prime untranslated regions (3'UTR) of mRNA at the consensus sequence motif CTCCA within hairpin loop structures [1]. This modification is involved in a potential quality-control mechanism related to translation termination, influencing mRNA and translation levels [1].

In terms of disease-related findings, in cervical cancer, NSUN6-mediated m5C modification of NDRG1 mRNA promotes radioresistance, and its overexpression is correlated with poor prognosis [2]. Biallelic pathogenic variants in NSUN6 cause autosomal recessive intellectual disability, as shown by identifying deleterious homozygous variants in affected individuals and observing locomotion and learning impairment in Drosophila with NSUN6 ortholog ablation [3]. In colon adenocarcinoma, NSUN6 promotes cell cycle progression and proliferation by upregulating METTL3 expression and catalyzing its m5C modification, and high expression is associated with shorter survival [4]. In lung cancer, NSUN6 restricts cell proliferation, migration, and epithelial-mesenchymal transition by regulating NM23-H1 expression through m5C modification of its 3'-UTR [5]. In glioblastoma, NSUN6 controls response to temozolomide via 5mC-mediated regulation of NELFB and RPS6BK2, with high expression conferring a survival benefit [6]. In pancreatic cancer, NSUN6 suppresses tumor development by regulating cell proliferation, and its reduction is a common feature [7]. In osteosarcoma, NSUN6 promotes tumor progression by upregulating EEF1A2 expression and activating the Akt/mTOR signaling pathway via m5C methylation [8].

In summary, NSUN6 is crucial for mRNA methylation, affecting translation termination and playing diverse roles in multiple diseases, including cancer and neurodevelopmental disorders. The study of NSUN6 in gene-knockout models, such as in Drosophila and potentially in KO/CKO mouse models in the future, helps to understand its function in specific biological processes and disease conditions, providing insights for potential therapeutic strategies.

References:

1. Selmi, Tommaso, Hussain, Shobbir, Dietmann, Sabine, Bornelöv, Susanne, Frye, Michaela. . Sequence- and structure-specific cytosine-5 mRNA methylation by NSUN6. In Nucleic acids research, 49, 1006-1022. doi:10.1093/nar/gkaa1193. https://pubmed.ncbi.nlm.nih.gov/33330931/

2. Yu, Min, Ni, Mengdong, Xu, Fei, Li, Jiajia, Ke, Guihao. 2024. NSUN6-mediated 5-methylcytosine modification of NDRG1 mRNA promotes radioresistance in cervical cancer. In Molecular cancer, 23, 139. doi:10.1186/s12943-024-02055-2. https://pubmed.ncbi.nlm.nih.gov/38970106/

3. Mattioli, Francesca, Worpenberg, Lina, Li, Cai-Tao, Roignant, Jean-Yves, Reymond, Alexandre. 2023. Biallelic variants in NSUN6 cause an autosomal recessive neurodevelopmental disorder. In Genetics in medicine : official journal of the American College of Medical Genetics, 25, 100900. doi:10.1016/j.gim.2023.100900. https://pubmed.ncbi.nlm.nih.gov/37226891/

4. Cui, Yuanbo, Lv, Pengju, Zhang, Chunyan. . NSUN6 mediates 5-methylcytosine modification of METTL3 and promotes colon adenocarcinoma progression. In Journal of biochemical and molecular toxicology, 38, e23749. doi:10.1002/jbt.23749. https://pubmed.ncbi.nlm.nih.gov/38800929/

5. Lu, Zhansheng, Liu, Bo, Kong, Demiao, Pei, Dengke, Liu, Di. 2023. NSUN6 Regulates NM23-H1 Expression in an m5C Manner to Affect Epithelial-Mesenchymal Transition in Lung Cancer. In Medical principles and practice : international journal of the Kuwait University, Health Science Centre, 33, 56-65. doi:10.1159/000535479. https://pubmed.ncbi.nlm.nih.gov/38029727/

6. Awah, Chidiebere U, Winter, Jan, Mazdoom, Claudiane M, Ogunwobi, Olorunseun O. 2021. NSUN6, an RNA methyltransferase of 5-mC controls glioblastoma response to temozolomide (TMZ) via NELFB and RPS6KB2 interaction. In Cancer biology & therapy, 22, 587-597. doi:10.1080/15384047.2021.1990631. https://pubmed.ncbi.nlm.nih.gov/34705606/

7. Yang, Ruimeng, Liang, Xing, Wang, Hui, Yang, Linhua, Zhan, Ming. 2021. The RNA methyltransferase NSUN6 suppresses pancreatic cancer development by regulating cell proliferation. In EBioMedicine, 63, 103195. doi:10.1016/j.ebiom.2020.103195. https://pubmed.ncbi.nlm.nih.gov/33418496/

8. Hu, Sang, Yang, Min, Xiao, Kangwen, Wang, Linlong, Wei, Renxiong. 2023. Loss of NSUN6 inhibits osteosarcoma progression by downregulating EEF1A2 expression and activation of Akt/mTOR signaling pathway via m5C methylation. In Experimental and therapeutic medicine, 26, 457. doi:10.3892/etm.2023.12156. https://pubmed.ncbi.nlm.nih.gov/37614424/