ANGEL2, a member of the CCR4 family of deadenylases, has 2',3'-cyclic phosphatase activity [2]. It is involved in RNA pathways that rely on the ligation or hydrolysis of 2',3'-cyclic phosphates, playing a role in pre-tRNA processing, XBP1 mRNA splicing during the unfolded protein response, and TRNT1-mediated CCA addition onto tRNAs [2]. Additionally, it has been associated with non-canonical mitochondrial RNA processing, where its phosphatase activity is required for the hydrolysis of 3' phosphates formed in this process [1].

Using Drosophila and mouse models, it was demonstrated that ANGEL2 is essential for non-canonical mitochondrial RNA processing [1]. In colon cancer cell lines, loss of ANGEL2 led to decreased expression of the tumor suppressor protein TP53, increased cell growth, and resistance to doxorubicin and etoposide [3]. ANGEL2 directly interacts with EIF4E, abrogating the interaction between the TP53 translation repressor RBM38 and EIF4E, thus enhancing TP53 translation [3].

In conclusion, ANGEL2 has crucial functions in RNA processing pathways, both in canonical and non-canonical contexts. Its role in modulating wildtype TP53 translation in colon cancer, as revealed by loss-of-function studies in cell lines, indicates its potential importance in cancer-related disease areas. The study of ANGEL2 using genetic models helps to understand its role in biological processes and disease mechanisms, potentially providing new insights for cancer treatment strategies.

References:

1. Clemente, Paula, Calvo-Garrido, Javier, Pearce, Sarah F, Freyer, Christoph, Wredenberg, Anna. 2022. ANGEL2 phosphatase activity is required for non-canonical mitochondrial RNA processing. In Nature communications, 13, 5750. doi:10.1038/s41467-022-33368-9. https://pubmed.ncbi.nlm.nih.gov/36180430/

2. Pinto, Paola H, Kroupova, Alena, Schleiffer, Alexander, Weitzer, Stefan, Martinez, Javier. . ANGEL2 is a member of the CCR4 family of deadenylases with 2',3'-cyclic phosphatase activity. In Science (New York, N.Y.), 369, 524-530. doi:10.1126/science.aba9763. https://pubmed.ncbi.nlm.nih.gov/32732418/

3. Lucchesi, Christopher August, Mantrala, Saisamkalpa, Tran, Darren, Ghosh, Paramita, Chen, Xinbin. 2025. ANGEL2 modulates wildtype TP53 translation and doxorubicin chemosensitivity in colon cancer. In Molecular cancer research : MCR, , . doi:10.1158/1541-7786.MCR-24-0702. https://pubmed.ncbi.nlm.nih.gov/40052999/