TSPYL5, also known as KIAA1750, is a member of the nucleosome assembly protein superfamily. It is involved in regulating various cellular functions, such as cell proliferation, apoptosis, and DNA damage response. TSPYL5 is associated with pathways like p53, USP7, and AKT/PTEN, and plays a crucial role in maintaining endothelial integrity, spermatogenesis, and tumorigenesis [1,2,3,4,5,6]. Genetic models, like knockout mouse models, have been valuable in studying its functions.

In Tspyl5 -knockout mice, male fertility declined, with reduced numbers of spermatogonia and spermatozoa in aged mice. Transcriptomic analysis revealed downregulation of the Pcna -mediated DNA replication pathway in spermatogonia from these knockout mice. TSPYL5 promotes spermatogonia proliferation by enhancing Pcna -mediated DNA replication through promoting the ubiquitination-degradation of the TRP53 protein [3]. In human endothelial cells, TSPYL5 overexpression promotes EC proliferation, migration, and tube formation by downregulating p53 expression, while TSPYL5 depletion-mediated loss of EC functions is blocked by p53 inhibition. TSPYL5 overexpression also promotes angiogenesis in Matrigel plug and wound repair in a mouse skin wound healing model in vivo [1]. In colorectal cancer, TSPYL5 overexpression inhibits tumorigenicity in vivo by inducing DNA damage, and in vitro, it suppresses cell proliferation, migration, and invasion, and induces apoptosis and endoplasmic reticulum stress [2,4].

In conclusion, TSPYL5 is crucial for spermatogenesis by enhancing DNA replication in spermatogonia. In endothelial cells, it maintains endothelial integrity and function. In colorectal cancer, it acts as a tumor suppressor. The Tspyl5 knockout mouse models have significantly contributed to understanding its role in male fertility-related processes and cancer-associated disease areas.

References:

1. Na, Hee-Jun, Yeum, Chung Eun, Kim, Han-Seop, Kim, Jae Yun, Cho, Yee Sook. 2018. TSPYL5-mediated inhibition of p53 promotes human endothelial cell function. In Angiogenesis, 22, 281-293. doi:10.1007/s10456-018-9656-z. https://pubmed.ncbi.nlm.nih.gov/30471052/

2. Huang, Chao, Ruan, Peng, He, Chunping, Zhou, Rui. . TSPYL5 inhibits the tumorigenesis of colorectal cancer cells in vivo by triggering DNA damage. In Journal of cancer research and therapeutics, 19, 898-903. doi:10.4103/jcrt.jcrt_1098_21. https://pubmed.ncbi.nlm.nih.gov/37675714/

3. Leng, Xiangyou, Xie, Shengyu, Tao, Dachang, Liu, Yunqiang, Yang, Yuan. . Mouse Tspyl5 promotes spermatogonia proliferation through enhancing Pcna-mediated DNA replication. In Reproduction, fertility, and development, 36, . doi:10.1071/RD23042. https://pubmed.ncbi.nlm.nih.gov/38185096/

4. Huang, Chao, He, Chunping, Ruan, Peng, Zhou, Rui. 2020. TSPYL5 activates endoplasmic reticulum stress to inhibit cell proliferation, migration and invasion in colorectal cancer. In Oncology reports, 44, 449-456. doi:10.3892/or.2020.7639. https://pubmed.ncbi.nlm.nih.gov/32627024/

5. Epping, Mirjam T, Meijer, Lars A T, Krijgsman, Oscar, Pandolfi, Pier Paolo, Bernards, René. 2010. TSPYL5 suppresses p53 levels and function by physical interaction with USP7. In Nature cell biology, 13, 102-8. doi:10.1038/ncb2142. https://pubmed.ncbi.nlm.nih.gov/21170034/

6. Kim, In-Gyu, Lee, Jei-Ha, Kim, Seo-Yeon, Kim, Rae-Kwon, Cho, Eun-Wie. 2021. Targeting therapy-resistant lung cancer stem cells via disruption of the AKT/TSPYL5/PTEN positive-feedback loop. In Communications biology, 4, 778. doi:10.1038/s42003-021-02303-x. https://pubmed.ncbi.nlm.nih.gov/34163000/