Dnmt1-KO Mouse

Dnmt1, or DNA methyltransferase 1, is the predominant member of the DNMT family and the most abundant DNMT in various cell types. It functions as a maintenance DNMT, playing a crucial role in maintaining DNA methylation patterns during DNA replication, which is essential for normal embryonic development, cell proliferation, and the regulation of gene expression. It is involved in multiple pathways such as those related to cell cycle regulation, apoptosis, and autophagy, and is associated with various diseases including cancer and nervous system diseases [2,3]. Genetic models, like KO/CKO mouse models, are valuable for studying its functions.

In triple-negative breast cancer (TNBC), Dnmt1 is overexpressed and plays oncogenic roles. It represses estrogen receptor (ER) expression, promotes epithelial-mesenchymal transition (EMT) for metastasis, induces cellular autophagy, and promotes the growth of cancer stem cells by hypermethylating the promoter regions of relevant genes [1]. In esophageal cancer, Dnmt1-mediated epigenetic suppression of FBXO32 expression promotes cyclin-dependent kinase 9 (CDK9) survival and cancer cell growth [5]. In human erythropoiesis, Dnmt1 deficiency leads to cell cycle arrest of erythroid progenitors and increased apoptosis during the terminal stage [4]. In acute lymphoblastic leukemia, exosomal Dnmt1 mRNA transcript is elevated, which might reprogram leukemia progression [6].

In conclusion, Dnmt1 is essential for maintaining DNA methylation and is involved in multiple biological processes. Its dysregulation is associated with various diseases, especially cancer. Studies using KO/CKO mouse models and other loss-of-function experiments have revealed its specific roles in disease-related biological processes, providing insights into potential therapeutic targets for these diseases.

References:

1. Wong, Kah Keng. 2020. DNMT1: A key drug target in triple-negative breast cancer. In Seminars in cancer biology, 72, 198-213. doi:10.1016/j.semcancer.2020.05.010. https://pubmed.ncbi.nlm.nih.gov/32461152/

2. Yan, Lan, Geng, Qi, Cao, Zhiwen, Zhao, Ning, Lu, Cheng. 2023. Insights into DNMT1 and programmed cell death in diseases. In Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 168, 115753. doi:10.1016/j.biopha.2023.115753. https://pubmed.ncbi.nlm.nih.gov/37871559/

3. Svedružić, Željko M. . Dnmt1 structure and function. In Progress in molecular biology and translational science, 101, 221-54. doi:10.1016/B978-0-12-387685-0.00006-8. https://pubmed.ncbi.nlm.nih.gov/21507353/

4. Yang, Qianqian, Chen, Lixiang, Zhang, Hengchao, An, Xiuli, Wang, Ting. 2024. DNMT1 regulates human erythropoiesis by modulating cell cycle and endoplasmic reticulum stress in a stage-specific manner. In Cell death and differentiation, 31, 999-1012. doi:10.1038/s41418-024-01305-6. https://pubmed.ncbi.nlm.nih.gov/38719927/

5. Song, Xian-Qiang, Chen, Bin-Bin, Jin, Yong-Mei, Wang, Chang-Yong. 2024. DNMT1-mediated epigenetic suppression of FBXO32 expression promoting cyclin dependent kinase 9 (CDK9) survival and esophageal cancer cell growth. In Cell cycle (Georgetown, Tex.), 23, 262-278. doi:10.1080/15384101.2024.2309022. https://pubmed.ncbi.nlm.nih.gov/38597826/

6. Haque, Shabirul, Vaiselbuh, Sarah R. 2021. Exosomal DNMT1 mRNA transcript is elevated in acute lymphoblastic leukemia which might reprograms leukemia progression. In Cancer genetics, 260-261, 57-64. doi:10.1016/j.cancergen.2021.07.004. https://pubmed.ncbi.nlm.nih.gov/34426211/