DIS3L2 is an RNA-binding protein with 3'-5' exoribonuclease activity. It contains RNA-binding domains like two CSD domains, one S1 domain, and an RNB domain for exoribonuclease activity. It is predominantly cytoplasmic and plays a crucial role in cytoplasmic RNA surveillance and decay, recognizing and degrading uridylated RNAs such as pre-microRNA, mature microRNA, mRNA, and non-coding RNAs. It is involved in multiple biological processes like cell division, proliferation, differentiation, and apoptosis. Genetic mouse models have been valuable for studying its functions [1].

In male mice, conditional ablation of Dis3l2 in pre-meiotic germ cells using Stra8-Cre mice leads to defective spermatogenesis and infertility. It disrupts spermatogonial differentiation, meiotic progression, and causes cell apoptosis. Bulk and scRNA-seq analyses show that Dis3l2 deficiency disturbs the transcriptional expression of genes related to the cell cycle, spermatogonial differentiation, and meiosis [2]. In female mice, oocyte-specific Dis3l2 knockout (Dis3l2cKO) results in almost all oocytes arresting at the germinal vesicle stage and female infertility. Uridylated-poly(A) RNAs accumulate in Dis3l2cKO oocytes due to insufficient degradation and stabilizing polyadenylation [3]. In Drosophila, a dis3L2 null mutant shows that its catalytic activity is required to control cell proliferation, and in human kidney HEK-293T cells, loss of DIS3L2 also leads to cell proliferation [4]. In colorectal cancer cells, DIS3L2 knockdown reduces the viability of highly oncogenic cells and disturbs metastasis-associated properties via the mTOR signaling pathway [5]. In hepatocellular carcinoma, DIS3L2 promotes cancer progression through hnRNP U-mediated alternative splicing [6].

In conclusion, DIS3L2 is essential for RNA degradation-mediated processes in spermatogenesis, oocyte maturation, cell proliferation, and tissue growth. The gene knockout and conditional knockout mouse models have significantly contributed to understanding its role in male and female infertility, as well as in cancer-related disease areas such as colorectal and liver cancers.

References:

1. Luan, Siyu, Luo, Junyun, Liu, Hui, Li, Zhaoyong. 2019. Regulation of RNA decay and cellular function by 3'-5' exoribonuclease DIS3L2. In RNA biology, 16, 160-165. doi:10.1080/15476286.2018.1564466. https://pubmed.ncbi.nlm.nih.gov/30638126/

2. Li, Nana, Yu, Junjie, Feng, Yan-Qin, Xu, Yu, Wang, Zhengpin. 2024. Conditional ablation of DIS3L2 ribonuclease in pre-meiotic germ cells causes defective spermatogenesis and infertility in male mice. In Theranostics, 14, 5621-5642. doi:10.7150/thno.98620. https://pubmed.ncbi.nlm.nih.gov/39310107/

3. Wu, Di, Pedroza, Monique, Chang, Jonathan, Dean, Jurrien. . DIS3L2 ribonuclease degrades terminal-uridylated RNA to ensure oocyte maturation and female fertility. In Nucleic acids research, 51, 3078-3093. doi:10.1093/nar/gkad061. https://pubmed.ncbi.nlm.nih.gov/36727488/

4. Towler, Benjamin P, Pashler, Amy L, Haime, Hope J, Arraiano, Cecilia M, Newbury, Sarah F. 2020. Dis3L2 regulates cell proliferation and tissue growth through a conserved mechanism. In PLoS genetics, 16, e1009297. doi:10.1371/journal.pgen.1009297. https://pubmed.ncbi.nlm.nih.gov/33370287/

5. García-Moreno, Juan F, Lacerda, Rafaela, da Costa, Paulo J, Matos, Paulo, Romão, Luísa. 2023. DIS3L2 knockdown impairs key oncogenic properties of colorectal cancer cells via the mTOR signaling pathway. In Cellular and molecular life sciences : CMLS, 80, 185. doi:10.1007/s00018-023-04833-5. https://pubmed.ncbi.nlm.nih.gov/37340282/

6. Xing, Songge, Li, Zhaoyong, Ma, Wenhao, Jia, Wei-Dong, Zhang, Huafeng. 2019. DIS3L2 Promotes Progression of Hepatocellular Carcinoma via hnRNP U-Mediated Alternative Splicing. In Cancer research, 79, 4923-4936. doi:10.1158/0008-5472.CAN-19-0376. https://pubmed.ncbi.nlm.nih.gov/31331910/