METTL16, an atypical methyltransferase, is responsible for depositing N6-methyladenosine (m6A) in certain transcripts and has functions related to RNA metabolism. It participates in various biological processes such as regulating SAM synthetase expression in response to SAM levels and is involved in pathways like translation initiation, BCAA metabolism, and glycolytic metabolism reprogramming [3,1,2,4]. Genetic models, especially KO/CKO mouse models, can be valuable for studying its functions.

In acute myeloid leukemia (AML), METTL16 is highly essential for AML cell survival, as its genetic depletion suppresses AML initiation/development and LSC/LIC self-renewal [2]. In hepatocellular carcinoma, liver-specific Mettl16 conditional KO (cKO) mice showed that METTL16 is crucial for tumorigenesis, and its depletion decreased liver CSC frequency [5]. In pancreatic ductal adenocarcinoma (PDAC), METTL16 can confer sensitivity to PARP inhibition [6].

In conclusion, METTL16 plays essential roles in gene regulation, with functions in both the nucleus and cytosol. Through model-based research, especially KO/CKO mouse models, it has been revealed to be involved in multiple disease-related processes, including leukemogenesis, liver cancer stem cell self-renewal, and response to PDAC treatment, highlighting its significance in understanding disease mechanisms and potential therapeutic strategies.

References:

1. Su, Rui, Dong, Lei, Li, Yangchan, He, Chuan, Chen, Jianjun. 2022. METTL16 exerts an m6A-independent function to facilitate translation and tumorigenesis. In Nature cell biology, 24, 205-216. doi:10.1038/s41556-021-00835-2. https://pubmed.ncbi.nlm.nih.gov/35145225/

2. Han, Li, Dong, Lei, Leung, Keith, Chen, Jianjun, Deng, Xiaolan. . METTL16 drives leukemogenesis and leukemia stem cell self-renewal by reprogramming BCAA metabolism. In Cell stem cell, 30, 52-68.e13. doi:10.1016/j.stem.2022.12.006. https://pubmed.ncbi.nlm.nih.gov/36608679/

3. Pendleton, Kathryn E, Chen, Beibei, Liu, Kuanqing, Tu, Benjamin P, Conrad, Nicholas K. . The U6 snRNA m6A Methyltransferase METTL16 Regulates SAM Synthetase Intron Retention. In Cell, 169, 824-835.e14. doi:10.1016/j.cell.2017.05.003. https://pubmed.ncbi.nlm.nih.gov/28525753/

4. Wei, Wei, Zhang, Zhong-Yuan, Shi, Bin, Jiang, Guan-Min, Wang, Hao. 2023. METTL16 promotes glycolytic metabolism reprogramming and colorectal cancer progression. In Journal of experimental & clinical cancer research : CR, 42, 151. doi:10.1186/s13046-023-02732-y. https://pubmed.ncbi.nlm.nih.gov/37340443/

5. Xue, Meilin, Dong, Lei, Zhang, Honghai, Chen, Hao, Su, Rui. 2024. METTL16 promotes liver cancer stem cell self-renewal via controlling ribosome biogenesis and mRNA translation. In Journal of hematology & oncology, 17, 7. doi:10.1186/s13045-024-01526-9. https://pubmed.ncbi.nlm.nih.gov/38302992/

6. Zeng, Xiangyu, Zhao, Fei, Cui, Gaofeng, Tao, Kaixiong, Lou, Zhenkun. 2022. METTL16 antagonizes MRE11-mediated DNA end resection and confers synthetic lethality to PARP inhibition in pancreatic ductal adenocarcinoma. In Nature cancer, 3, 1088-1104. doi:10.1038/s43018-022-00429-3. https://pubmed.ncbi.nlm.nih.gov/36138131/