Ensa, also known as α -endosulfine, is an essential regulator in the cell cycle. It is part of the Greatwall (GWL)/Ensa/PP2A-B55 pathway, which controls mitotic substrate phosphorylation and mitotic entry. Ensa can be phosphorylated by GWL, turning it into a potent inhibitor of PP2A-B55 phosphatase, thus indirectly regulating cyclin B/CDK1 activity during mitosis [1,2,3,6,7,8]. This pathway is crucial for various biological processes such as DNA replication and cell cycle progression, and understanding Ensa's function can provide insights into normal and abnormal cellular development [1,2].

Using conditional knockout mouse models, researchers found that Ensa is not essential for mouse embryogenesis, unlike its paralog Arpp19 [1]. Ensa gene ablation perturbed the S phase, while Arpp19 knockout did not [1]. In human cells, Ensa knockdown led to a dramatic extension of S phase associated with a lowered density of replication forks, possibly due to decreased levels of Treslin, a key protein for replication origin firing [2]. In mouse oocytes, Ensa plays a key role in the progression from prophase I arrest into M-phase of meiosis I, with ENSA-deficient oocytes mostly failing to exit prophase I arrest [7].

In summary, Ensa is vital in regulating the cell cycle, especially in S-phase length control and meiotic maturation. Mouse knockout models have revealed its specific non-essential role in embryogenesis but importance in other cellular processes. In diseases, such as triple-negative breast cancer where ENSA amplification promotes tumor progression via cholesterol biosynthesis [4], and in oral squamous cell carcinoma where the MASTL-ENSA-PP2A/B55 axis modulates cisplatin resistance [5], understanding Ensa's function could potentially lead to new therapeutic strategies.

References:

1. Hached, Khaled, Goguet, Perrine, Charrasse, Sophie, Lorca, Thierry, Castro, Anna. 2019. ENSA and ARPP19 differentially control cell cycle progression and development. In The Journal of cell biology, 218, 541-558. doi:10.1083/jcb.201708105. https://pubmed.ncbi.nlm.nih.gov/30626720/

2. Charrasse, Sophie, Gharbi-Ayachi, Aicha, Burgess, Andrew, Lorca, Thierry, Castro, Anna. 2017. Ensa controls S-phase length by modulating Treslin levels. In Nature communications, 8, 206. doi:10.1038/s41467-017-00339-4. https://pubmed.ncbi.nlm.nih.gov/28785014/

3. Thapa, Chandan, Roivas, Pekka, Haataja, Tatu, Permi, Perttu, Pentikäinen, Ulla. 2021. Interaction mechanism of endogenous PP2A inhibitor protein ENSA with PP2A. In The FEBS journal, 289, 519-534. doi:10.1111/febs.16150. https://pubmed.ncbi.nlm.nih.gov/34346186/

4. Chen, Yi-Yu, Ge, Jing-Yu, Zhu, Si-Yuan, Shao, Zhi-Ming, Yu, Ke-Da. 2022. Copy number amplification of ENSA promotes the progression of triple-negative breast cancer via cholesterol biosynthesis. In Nature communications, 13, 791. doi:10.1038/s41467-022-28452-z. https://pubmed.ncbi.nlm.nih.gov/35145111/

5. Gouttia, Odjo G, Zhao, Jing, Li, Yanqiu, Oakley, Gregory G, Peng, Aimin. 2022. The MASTL-ENSA-PP2A/B55 axis modulates cisplatin resistance in oral squamous cell carcinoma. In Frontiers in cell and developmental biology, 10, 904719. doi:10.3389/fcell.2022.904719. https://pubmed.ncbi.nlm.nih.gov/36247015/

6. Labandera, Anne-Marie, Vahab, Ahmad R, Chaudhuri, Sibapriya, Kerk, David, Moorhead, Greg B G. 2015. The mitotic PP2A regulator ENSA/ARPP-19 is remarkably conserved across plants and most eukaryotes. In Biochemical and biophysical research communications, 458, 739-44. doi:10.1016/j.bbrc.2015.01.123. https://pubmed.ncbi.nlm.nih.gov/25666948/

7. Matthews, Lauren M, Evans, Janice P. 2014. α-endosulfine (ENSA) regulates exit from prophase I arrest in mouse oocytes. In Cell cycle (Georgetown, Tex.), 13, 1639-49. doi:10.4161/cc.28606. https://pubmed.ncbi.nlm.nih.gov/24675883/

8. Kumm, Elena J, Pagel, Oliver, Gambaryan, Stepan, Smolenski, Albert, Jurk, Kerstin. 2020. The Cell Cycle Checkpoint System MAST(L)-ENSA/ARPP19-PP2A is Targeted by cAMP/PKA and cGMP/PKG in Anucleate Human Platelets. In Cells, 9, . doi:10.3390/cells9020472. https://pubmed.ncbi.nlm.nih.gov/32085646/