Nono-KO Mouse

NONO, also known as non-POU domain-containing octamer-binding protein/p54nrb, is a multifunctional nuclear protein belonging to the Drosophila behaviour/human splicing (DBHS) family. It functions as a “molecular scaffold” and is involved in almost every step of gene regulation, including mRNA splicing, DNA unwinding, transcriptional regulation, nuclear retention of defective RNA, and DNA repair. It participates in numerous biological processes such as cell proliferation, apoptosis, migration, DNA damage repair, and also plays roles in maintaining cellular circadian rhythm coupled to the cell cycle [1,4]. Genetic models, like knockout (KO) mouse models, are valuable for studying NONO's functions [3].

In mice, global deletion of NONO impairs early B-cell development at the pro-to pre-B-cell transition stage and B-cell maturation in the spleen, while BM chimeric mice studies show this impairment is B-cell-intrinsic. NONO-deficient B cells have increased BCR-induced apoptosis and impaired activation of ERK, AKT, and NF-κB pathways [3]. In smooth muscle-specific NONO-knockout mice, they are more susceptible to vascular calcification, with increased calcification severity and calcium deposition, indicating NONO is a negative regulator of vascular calcification [2]. In the murine KP (KRasG12D, Trp53-/-) cell-based lung cancer model, deletion of Nono impairs the response to DNA damage, showing hyperactivation of DSB signalling and high levels of DSBs, along with reduced RNA polymerase II promoter occupancy and attenuated induction of Gadd45b [5].

In conclusion, NONO is a key regulator in multiple biological processes. Model-based research, especially KO mouse models, has revealed its significance in B-cell development, vascular calcification, and DNA repair. Understanding NONO's functions provides insights into the mechanisms of related diseases, potentially offering new therapeutic targets for conditions like B-cell-related disorders, vascular calcification, and cancers where DNA repair dysregulation is involved [2,3,5].

References:

1. Feng, Peifu, Li, Ling, Deng, Tanggang, Zhang, Lei, Ye, Mao. 2020. NONO and tumorigenesis: More than splicing. In Journal of cellular and molecular medicine, 24, 4368-4376. doi:10.1111/jcmm.15141. https://pubmed.ncbi.nlm.nih.gov/32168434/

2. Lu, Yue, Meng, Linlin, Ren, Ruiqing, Zhang, Yun, Zhang, Cheng. 2024. Paraspeckle protein NONO attenuates vascular calcification by inhibiting bone morphogenetic protein 2 transcription. In Kidney international, 105, 1221-1238. doi:10.1016/j.kint.2024.01.039. https://pubmed.ncbi.nlm.nih.gov/38417578/

3. Zhang, Yongguang, Cui, Dongya, Huang, Miaohui, Chen, Liling, Chen, Qi. . NONO regulates B-cell development and B-cell receptor signaling. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 37, e22862. doi:10.1096/fj.202201909RR. https://pubmed.ncbi.nlm.nih.gov/36906291/

4. Ronchetti, Domenica, Traini, Valentina, Silvestris, Ilaria, Bolli, Niccolò, Taiana, Elisa. 2024. The pleiotropic nature of NONO, a master regulator of essential biological pathways in cancers. In Cancer gene therapy, 31, 984-994. doi:10.1038/s41417-024-00763-x. https://pubmed.ncbi.nlm.nih.gov/38493226/

5. Mamontova, Victoria, Trifault, Barbara, Burger, Kaspar. 2024. Nono induces Gadd45b to mediate DNA repair. In Life science alliance, 7, . doi:10.26508/lsa.202302555. https://pubmed.ncbi.nlm.nih.gov/38843934/