TUT1, short for terminal uridylyltransferase 1, is a key regulator within the U4/U6 spliceosome. It catalyzes the oligo-uridylylation of U6 small nuclear RNA (snRNA), which is essential for U6 snRNA maturation, U4/U6-di-snRNP formation, and U6 snRNA recycling during pre-mRNA splicing. RNA uridylylation, a process TUT1 is involved in, plays a pivotal role in the biogenesis and metabolism of functional RNAs and regulates cellular gene expression [1].

In a study on pancreatic ductal adenocarcinoma (PDAC), depletion of TUT1 in PDAC cells led to inefficient splicing of exons in highly expressed RNAs with weak splice sites, collapsing the mRNA processing circuit and dysregulating splicing required by PDAC cells. This shows that TUT1 is required for the survival of PDAC cells but not for normal pancreatic cells [2]. In osteosarcoma, TUT1 was found to be significantly downregulated compared with adjacent normal tissues. Enforced expression of TUT1 inhibited cell proliferation, while its knockdown promoted it. TUT1 inhibited the expression of key lipogenesis regulators, PPARγ and SREBP-1c, through upregulating microRNA-24 and microRNA-29a, suggesting it may act as a tumor suppressor [3]. In Talaromyces marneffei infection, TUT1 was identified as the alternative splicing (AS) regulator that promotes the production of a truncated protein of NCOR2/SMRT, named NCOR2-013, which forms a co-repression complex to inhibit JunB-mediated transcriptional activation of pro-inflammatory cytokines, thus promoting the fungus' immune evasion [4].

In summary, TUT1 plays crucial roles in RNA metabolism, especially in pre-mRNA splicing. Its functions are also implicated in diseases such as pancreatic cancer, osteosarcoma, and fungal immune evasion. Research on TUT1 using models like gene depletion in cancer cells helps to understand its role in disease-related biological processes, potentially providing new targets for disease treatment.

References:

1. Yashiro, Yuka, Tomita, Kozo. 2018. Function and Regulation of Human Terminal Uridylyltransferases. In Frontiers in genetics, 9, 538. doi:10.3389/fgene.2018.00538. https://pubmed.ncbi.nlm.nih.gov/30483311/

2. Guo, Ziwei, Huang, Junran, Lu, Zhi J, David, Charles J, Chen, Mo. . Targeting TUT1 Depletes Tri-snRNP Pools to Suppress Splicing and Inhibit Pancreatic Cancer Cell Survival. In Cancer research, 85, 1270-1286. doi:10.1158/0008-5472.CAN-24-2563. https://pubmed.ncbi.nlm.nih.gov/39854320/

3. Zhu, De-Qiu, Lou, Yue-Fen, He, Zhi-Gao, Ji, Min. 2014. Nucleotidyl transferase TUT1 inhibits lipogenesis in osteosarcoma cells through regulation of microRNA-24 and microRNA-29a. In Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, 35, 11829-35. doi:10.1007/s13277-014-2395-x. https://pubmed.ncbi.nlm.nih.gov/25142229/

4. Wei, Wudi, Wang, Gang, Zhang, Hong, Ye, Li, Liang, Hao. 2023. Talaromyces marneffei suppresses macrophage inflammation by regulating host alternative splicing. In Communications biology, 6, 1046. doi:10.1038/s42003-023-05409-6. https://pubmed.ncbi.nlm.nih.gov/37845378/