Dut-KO Mouse

DUT, encoding deoxyuridine triphosphatase, is the only known dUTPase in humans and plays a crucial role in nucleotide metabolism. It helps prevent uracil misincorporation during DNA replication, which is a major cell-toxic event [4]. There are multiple isoforms of DUT, including nuclear (DUT-N), mitochondrial (DUT-M), DUT-3 without any localization signal, and DUT-4 with the same nuclear localization signal as DUT-N [2]. DUT-M is also involved in RLR-VISA-mediated antiviral signaling, facilitating the assembly of the VISA-TRAF2 complex [3].

In multiple myeloma, DUT knockdown by RNAi effectively minimized bortezomib (BTZ) resistance, accompanied by down-regulation of PCNA, decelerated cell growth, and augmented apoptosis due to BTZ treatment. In contrast, DUT overexpression enhanced BTZ resistance. Also, DUT inhibition could attenuate mitochondrial modulation and overcome drug resistance to BTZ both in vitro and in vivo [1]. In hepatocellular carcinoma (HCC), DUT knockout in cell lines suppressed proliferation through cell-cycle arrest and induced DNA damage, and targeting dUTPase activity could potentiate suppression of HCC growth [4].

In conclusion, DUT is essential for nucleotide metabolism and maintaining genomic stability. Its role in drug resistance in multiple myeloma and proliferation in HCC, as revealed by knockdown and knockout studies, highlights its potential as a therapeutic target in these diseases. These functional studies using loss-of-function models contribute to understanding the underlying mechanisms of diseases and offer new perspectives for treatment strategies.

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/