Dut-KO Mouse

DUT, encoding deoxyuridine triphosphatase, is the only known dUTPase in humans. This enzyme is crucial in nucleotide metabolism, preventing uracil misincorporation during DNA replication, a major cell-toxic event [4]. There are multiple isoforms of DUT, including nuclear (DUT-N), mitochondrial (DUT-M), DUT-3 without a localization signal, and DUT-4 with the same nuclear localization signal as DUT-N [2].

In multiple myeloma, DUT enhances drug resistance to proteasome inhibitors like bortezomib. Knockdown of DUT by RNAi minimized bortezomib resistance, decelerated cell growth, and augmented apoptosis [1]. In hepatocellular carcinoma, knockout of DUT in cell lines suppressed proliferation through cell-cycle arrest and induced DNA damage. Targeting DUT's dUTPase activity could enhance the suppression of HCC growth [4]. Mitochondrial DUT-M acts as a positive regulator in RLR-VISA-mediated antiviral signaling. DUT-M interacts with VISA and RIG-I, facilitating VISA-TRAF2 complex assembly and enhancing the innate immune response. DUT-knockdown and DUT-deficient 293 cells inhibited this signaling [3].

In conclusion, DUT is essential for nucleotide metabolism and preventing DNA replication-related cell toxicity. Its isoforms play various roles in different biological processes. Research on DUT knockout models has revealed its implications in multiple myeloma, hepatocellular carcinoma, and antiviral innate immune response, providing potential therapeutic targets for these disease areas.

References:

1. Wang, Yafei, Gao, Shuang, Chen, Lin, Cao, Zeng, Li, Qian. . DUT enhances drug resistance to proteasome inhibitors via promoting mitochondrial function in multiple myeloma. In Carcinogenesis, 43, 1030-1038. doi:10.1093/carcin/bgac071. https://pubmed.ncbi.nlm.nih.gov/36426924/

2. Rácz, Gergely Attila, Nagy, Nikolett, Várady, György, Apáti, Ágota, Vértessy, Beáta G. 2023. Discovery of two new isoforms of the human DUT gene. In Scientific reports, 13, 7760. doi:10.1038/s41598-023-32970-1. https://pubmed.ncbi.nlm.nih.gov/37173337/

3. Weng, Guang-Xiu, Ling, Ting, Hou, Wen, Wang, Dan-Dan, Xu, Liang-Guo. 2021. Mitochondrial DUT-M potentiates RLR-mediated antiviral signaling by enhancing VISA and TRAF2 association. In Molecular immunology, 132, 117-125. doi:10.1016/j.molimm.2021.01.023. https://pubmed.ncbi.nlm.nih.gov/33582548/

4. Xu, Mingjing, Liu, Yue, Wan, Ho Lee, Ng, Kelvin K-C, Wong, Nathalie. 2022. Overexpression of nucleotide metabolic enzyme DUT in hepatocellular carcinoma potentiates a therapeutic opportunity through targeting its dUTPase activity. In Cancer letters, 548, 215898. doi:10.1016/j.canlet.2022.215898. https://pubmed.ncbi.nlm.nih.gov/36075487/