Nsun5, also known as NOP2/Sun RNA methyltransferase 5, is an enzyme belonging to the 5-methylcytosine (m5C) writer family, which modifies rRNA and mRNA. It is involved in multiple biological processes, including ferroptosis, immune evasion, maternal-to-zygotic transition, lipid metabolism, and tumor progression. Its associated pathways include the NSUN5-FTH1/FTL pathway in ferroptosis, and it plays a role in regulating RNA metabolism and the Hippo signaling pathway [1,2,3,6].

In mouse models, Nsun5 knockout leads to various impairments. Nsun5KO in mouse ovaries obstructs follicular development and ovarian function, inhibiting embryogenesis and embryo development due to a decline in m5C in the exon and 3'UTR regions affecting the translation of related genes [3]. In preimplantation embryos, Nsun5 knockdown causes reduced blastocyst formation, smaller blastocysts, impaired hatching, decreased cell numbers, increased apoptosis, and disrupted cell differentiation through the Hippo signaling pathway [6]. In glioma, Nsun5-directed chromatin-associated RNA modification is involved in immune evasion [2]. In cancer studies, Nsun5 promotes tumor progression. For example, in hepatocellular carcinoma, its overexpression strengthens ribosome functions and global protein translation, promoting proliferation and migration. In gastric cancer, the NSUN5-FTH1 axis inhibits ferroptosis to promote cancer cell growth [4,5].

In summary, Nsun5 is essential for normal biological processes such as embryonic development and ovarian function. Its dysregulation is closely associated with various diseases, especially cancers. The use of Nsun5 knockout or knockdown mouse models has significantly contributed to understanding its role in these biological processes and diseases, providing potential targets for therapeutic interventions.

References:

1. Liu, Jie, Ren, Zhenxing, Yang, Lin, Zhu, Meiling, Kuang, Weihong. 2022. The NSUN5-FTH1/FTL pathway mediates ferroptosis in bone marrow-derived mesenchymal stem cells. In Cell death discovery, 8, 99. doi:10.1038/s41420-022-00902-z. https://pubmed.ncbi.nlm.nih.gov/35249107/

2. Wu, Ruixin, Sun, Chunming, Chen, Xi, Dai, Haochen, Shu, Minfeng. 2024. NSUN5/TET2-directed chromatin-associated RNA modification of 5-methylcytosine to 5-hydroxymethylcytosine governs glioma immune evasion. In Proceedings of the National Academy of Sciences of the United States of America, 121, e2321611121. doi:10.1073/pnas.2321611121. https://pubmed.ncbi.nlm.nih.gov/38547058/

3. Ding, Chenyue, Lu, Jiafeng, Li, Jincheng, Li, Hong, Huang, Boxian. . RNA-methyltransferase Nsun5 controls the maternal-to-zygotic transition by regulating maternal mRNA stability. In Clinical and translational medicine, 12, e1137. doi:10.1002/ctm2.1137. https://pubmed.ncbi.nlm.nih.gov/36495115/

4. Zhang, Xiao-Wen, Wu, Lu-Yi, Liu, Hui-Rong, Yu, Jian, Wu, Huan-Gan. 2022. NSUN5 promotes progression and predicts poor prognosis in hepatocellular carcinoma. In Oncology letters, 24, 439. doi:10.3892/ol.2022.13559. https://pubmed.ncbi.nlm.nih.gov/36420066/

5. Su, Yibin, Liu, Jiangrui, Zheng, Zhihua, Wang, Weidong, Zhuang, Haibin. 2023. NSUN5-FTH1 Axis Inhibits Ferroptosis to Promote the Growth of Gastric Cancer Cells. In Cell biochemistry and biophysics, 81, 553-560. doi:10.1007/s12013-023-01152-1. https://pubmed.ncbi.nlm.nih.gov/37528314/

6. Liu, Dan, Yamamoto, Takuto, Wang, Haoxue, Honda, Shinnosuke, Ikeda, Shuntaro. 2024. NSUN5 is essential for proper cell proliferation and differentiation of mouse preimplantation embryos. In Reproduction (Cambridge, England), 168, . doi:10.1530/REP-24-0079. https://pubmed.ncbi.nlm.nih.gov/38670153/