NUDT21, also known as CFIm25 (mammalian cleavage factor I subunit) or CPSF5, is a crucial RNA-binding protein. It binds to UGUA sequences of precursor RNAs and is involved in multiple RNA processing events such as alternative polyadenylation (APA), which generates different 3' UTR lengths of transcripts from the same gene, influencing mRNA stability and translation. APA regulated by NUDT21 is involved in various biological processes like spermatogenesis and cell fate determination, and is associated with multiple diseases including cancer, neural dysfunction, and fibrosis [2,6].

In B-cell acute lymphoblastic leukemia (B-ALL), NUDT21 limits CD19 levels through alternative mRNA polyadenylation. Deletion of NUDT21 in B-ALL cells increased CD19 expression and sensitivity to CD19-specific immunotherapies [1]. In renal fibrosis, the E3 ligase TRIM65 interacts with NUDT21, leading to its degradation and altering the 3'UTR-APA of pro-fibrotic genes. Reducing NUDT21 expression via AAV9 injection exacerbated UUO-induced renal fibrosis [3]. In pancreatic cancer, NUDT21 promotes the usage of proximal polyadenylation sites on MZT1 mRNA, contributing to cancer progression [4]. In glioma, NUDT21 knockdown promotes glioma cell migration by causing 3'UTR shortening of LAMC1 [5]. In macrophages, Nudt21 depletion in myeloid-specific Nudt21-deficient mice protects against colitis and hyperinflammation through regulating autophagy-related genes' mRNA stability [7].

In summary, NUDT21-mediated APA is essential in various biological processes and disease conditions. Gene knockout or knockdown models in different cell types and animal models have revealed its role in cancer, fibrosis, and inflammation-related diseases, providing insights into potential therapeutic strategies targeting NUDT21-regulated pathways.

References:

1. Witkowski, Matthew T, Lee, Soobeom, Wang, Eric, Eyquem, Justin, Aifantis, Iannis. 2022. NUDT21 limits CD19 levels through alternative mRNA polyadenylation in B cell acute lymphoblastic leukemia. In Nature immunology, 23, 1424-1432. doi:10.1038/s41590-022-01314-y. https://pubmed.ncbi.nlm.nih.gov/36138187/

2. Xiao, Shan, Gu, Huan, Deng, Li, Zhang, Tian, Yu, Tao. 2023. Relationship between NUDT21 mediated alternative polyadenylation process and tumor. In Frontiers in oncology, 13, 1052012. doi:10.3389/fonc.2023.1052012. https://pubmed.ncbi.nlm.nih.gov/36816917/

3. Wei, Sisi, Huang, Xuan, Zhu, Qing, Lei, Enjun, Li, Yong. 2024. TRIM65 deficiency alleviates renal fibrosis through NUDT21-mediated alternative polyadenylation. In Cell death and differentiation, 31, 1422-1438. doi:10.1038/s41418-024-01336-z. https://pubmed.ncbi.nlm.nih.gov/38951701/

4. Zhou, Yu, Yang, Jiabin, Huang, Leyi, Chen, Rufu, Zhou, Quanbo. 2024. Nudt21-mediated alternative polyadenylation of MZT1 3'UTR contributes to pancreatic cancer progression. In iScience, 27, 108822. doi:10.1016/j.isci.2024.108822. https://pubmed.ncbi.nlm.nih.gov/38303721/

5. Jonnakuti, Venkata Soumith, Ji, Ping, Gao, Yipeng, Yalamanchili, Hari Krishna, Wagner, Eric J. 2023. NUDT21 alters glioma migration through differential alternative polyadenylation of LAMC1. In Journal of neuro-oncology, 163, 623-634. doi:10.1007/s11060-023-04370-y. https://pubmed.ncbi.nlm.nih.gov/37389756/

6. Masamha, Chioniso Patience. 2022. The emerging roles of CFIm25 (NUDT21/CPSF5) in human biology and disease. In Wiley interdisciplinary reviews. RNA, 14, e1757. doi:10.1002/wrna.1757. https://pubmed.ncbi.nlm.nih.gov/35965101/

7. Chen, Yunzhu, Chen, Baiwen, Li, Jingyu, Wang, Zhengting, Li, Hua-Bing. 2024. Alternative mRNA polyadenylation regulates macrophage hyperactivation via the autophagy pathway. In Cellular & molecular immunology, 21, 1522-1534. doi:10.1038/s41423-024-01237-8. https://pubmed.ncbi.nlm.nih.gov/39537902/