ENDOD1, also known as NUMEN, is a transmembrane nuclease that plays a crucial role in DNA repair [1]. It is a member of the DNA/RNA non-specific nucleases family. ENDOD1 is involved in regulating DNA repair pathway choice, especially in compartmentalized and non-homologous end joining-dependent repair of double-stranded DNA breaks at the nuclear periphery. It also functions in innate immunity, and is associated with pathways like cGAS-STING [2,4].

In ENDOD1-deficient cells, there are increased PARP chromatin-association and DNA double-strand breaks accumulate, especially when combined with homologous recombination defects [2]. ENDOD1-deficient cells also show synthetic lethality with p53-mutated tumour cells. Systemic knockdown of mouse EndoD1 is well-tolerated, and whole-animal siRNA against human ENDOD1 restrains TP53-mutated tumour progression in xenograft models [2]. In prostate cancer cell lines, overexpression of ENDOD1 suppresses cell proliferation, induces G0/G1 cell cycle arrest and inhibits cell migration and invasion, indicating it may act as a tumour suppressor [3].

In conclusion, ENDOD1 is essential for DNA repair pathway choice and genome-stability maintenance. Studies using gene-knockout models, such as knockdown in mouse and cell-line-based loss-of-function experiments, have revealed its role in cancer-related processes. These findings suggest ENDOD1 has potential as a target for synthetic lethal treatments in p53-mutated tumours and as a new drug target in prostate cancer [2,3].

References:

1. Chen, Bohong, Ge, Tianyu, Jian, Meiqi, Ma, Wenbin, Songyang, Zhou. 2023. Transmembrane nuclease NUMEN/ENDOD1 regulates DNA repair pathway choice at the nuclear periphery. In Nature cell biology, 25, 1004-1016. doi:10.1038/s41556-023-01165-1. https://pubmed.ncbi.nlm.nih.gov/37322289/

2. Tang, Zizhi, Zeng, Ming, Wang, Xiaojun, Carr, Antony M, Liu, Cong. 2022. Synthetic lethality between TP53 and ENDOD1. In Nature communications, 13, 2861. doi:10.1038/s41467-022-30311-w. https://pubmed.ncbi.nlm.nih.gov/35606358/

3. Qiu, Jianguang, Peng, Shubin, Si-Tu, Jie, Li, Ke, Wang, Dejuan. 2017. Identification of endonuclease domain-containing 1 as a novel tumor suppressor in prostate cancer. In BMC cancer, 17, 360. doi:10.1186/s12885-017-3330-5. https://pubmed.ncbi.nlm.nih.gov/28532481/

4. Fenech, Emma J, Lari, Federica, Charles, Philip D, Kessler, Benedikt M, Christianson, John C. 2020. Interaction mapping of endoplasmic reticulum ubiquitin ligases identifies modulators of innate immune signalling. In eLife, 9, . doi:10.7554/eLife.57306. https://pubmed.ncbi.nlm.nih.gov/32614325/