Dcps-KO Mouse

Dcps, also known as the decapping scavenger enzyme, is a key player in mRNA metabolism. It carries out the final step of the 3' to 5' end mRNA decay pathway by hydrolyzing the residual cap structure (m(7)GpppN) to m(7)GMP and NDP, preventing the accumulation of short mRNA fragments that could inhibit cap-binding proteins [1,2]. This function implies its potential role in modulating various mRNA-related processes such as pre-mRNA splicing, nuclear export, translation, and decay, as the 5' cap and cap-binding proteins are integral to these processes [1].

In the developing mouse neocortex, DcpS is required for the radial migration, polarity, neurite outgrowth, and identity of developing glutamatergic neurons. Homozygous mutations in the DcpS-encoding gene lead to compromised neuronal differentiation and neurite outgrowth in human neurons derived from patients, highlighting its importance in neural development [4]. In glioblastoma, DcpS is overexpressed and associated with poor patient survival. The DcpS inhibitor RG3039 shows anti-glioblastoma activities in cell lines, patient-derived organoids, and orthotopic mouse models by downregulating STAT5B expression [3]. In uveal melanoma, inhibition of DcpS by shRNA or RG3039 induces ferroptosis, reduces cancer stem-like cells, and hampers tumor growth and hepatic metastasis [5]. Also, in mammalian cells, DcpS, in conjunction with Xrn1, can regulate RNA stability in a transcript-selective manner [6].

In conclusion, DcpS is essential for mRNA metabolism and plays significant roles in neural development and various disease conditions such as glioblastoma and uveal melanoma. Studies using loss-of-function models, like patient-derived cells with DcpS mutations and inhibitor-treated models in vivo, have revealed its functions in specific biological processes and disease mechanisms, providing potential therapeutic targets for these diseases.

References:

1. Bail, Sophie, Kiledjian, Megerditch. 2008. DcpS, a general modulator of cap-binding protein-dependent processes? In RNA biology, 5, 216-9. doi:. https://pubmed.ncbi.nlm.nih.gov/18948758/

2. Milac, Adina L, Bojarska, Elzbieta, Wypijewska del Nogal, Anna. 2014. Decapping Scavenger (DcpS) enzyme: advances in its structure, activity and roles in the cap-dependent mRNA metabolism. In Biochimica et biophysica acta, 1839, 452-62. doi:10.1016/j.bbagrm.2014.04.007. https://pubmed.ncbi.nlm.nih.gov/24742626/

3. Duan, Hao, Xie, Yuan, Wu, Suwen, Ma, Wenjuan, Mou, Yonggao. 2024. Effect of the mRNA decapping enzyme scavenger (DCPS) inhibitor RG3039 on glioblastoma. In Journal of translational medicine, 22, 880. doi:10.1186/s12967-024-05658-x. https://pubmed.ncbi.nlm.nih.gov/39350123/

4. Salamon, Iva, Palsule, Geeta, Luo, Xiaobing, Rasin, Mladen-Roko, Kiledjian, Megerditch. . mRNA-Decapping Associated DcpS Enzyme Controls Critical Steps of Neuronal Development. In Cerebral cortex (New York, N.Y. : 1991), 32, 1494-1507. doi:10.1093/cercor/bhab302. https://pubmed.ncbi.nlm.nih.gov/34467373/

5. Jin, Bei, Yang, Luo, Ye, Qianyun, Pan, Jingxuan. 2023. Ferroptosis induced by DCPS depletion diminishes hepatic metastasis in uveal melanoma. In Biochemical pharmacology, 213, 115625. doi:10.1016/j.bcp.2023.115625. https://pubmed.ncbi.nlm.nih.gov/37245534/

6. Zhou, Mi, Bail, Sophie, Plasterer, Heather L, Rusche, James, Kiledjian, Megerditch. 2015. DcpS is a transcript-specific modulator of RNA in mammalian cells. In RNA (New York, N.Y.), 21, 1306-12. doi:10.1261/rna.051573.115. https://pubmed.ncbi.nlm.nih.gov/26001796/