Rnf8, also known as really interesting new gene (RING) finger protein 8, is a central factor in DNA double strand break (DSB) signal transduction. It is an E3 ligase that catalyzes histone ubiquitination, which is crucial for regulating chromatin structure in processes like the DNA damage response (DDR), telomere protection, cell cycle control, and transcriptional regulation [2,3].

Loss of Rnf8 significantly protects Brca1-mutant mice against mammary tumorigenesis. In human BRCA1-mutant breast cancer cells, Rnf8 deficiency promotes R-loop accumulation, replication fork instability, and increased DNA damage, leading to senescence and synthetic lethality. Mechanistically, Rnf8 interacts with XRN2 and ubiquitylates it to facilitate R-loop resolution [1]. Rnf8 knockout mice display phenotypes associated with failed DDR, such as hypersensitivity to ionizing radiation, V(D)J recombination deficiency, and a predisposition to cancer. They also fail to generate mature sperm during spermatogenesis, resulting in male sterility [3]. In hepatocellular carcinoma (HCC), silencing Rnf8 by siRNAs attenuates cell migration and inhibits epithelial-mesenchymal transition (EMT), and Rnf8 depletion enhances the sensitivity of HCC cells to sorafenib and lenvatinib treatment [4]. In lung cancer cells, overexpression of Rnf8 promotes the EMT process and migration ability, while knockdown shows opposite effects [5].

In conclusion, Rnf8 plays essential roles in DNA damage response, spermatogenesis, and tumorigenesis. Gene knockout mouse models have been instrumental in revealing its functions in processes related to genomic instability and cancer development, such as in BRCA1-mutant-associated breast cancer, HCC, and lung cancer. These findings suggest that Rnf8 could be a potential therapeutic target in certain cancers [1,4,5].

References:

1. Krishnan, Rehna, Lapierre, Mariah, Gautreau, Brandon, Hakem, Anne, Hakem, Razqallah. . RNF8 ubiquitylation of XRN2 facilitates R-loop resolution and restrains genomic instability in BRCA1 mutant cells. In Nucleic acids research, 51, 10484-10505. doi:10.1093/nar/gkad733. https://pubmed.ncbi.nlm.nih.gov/37697435/

2. Zhou, Tingting, Yi, Fei, Wang, Zhuo, Cao, Liu, Song, Xiaoyu. 2019. The Functions of DNA Damage Factor RNF8 in the Pathogenesis and Progression of Cancer. In International journal of biological sciences, 15, 909-918. doi:10.7150/ijbs.31972. https://pubmed.ncbi.nlm.nih.gov/31182912/

3. Ma, Teng, Keller, Jennifer A, Yu, Xiaochun. 2011. RNF8-dependent histone ubiquitination during DNA damage response and spermatogenesis. In Acta biochimica et biophysica Sinica, 43, 339-45. doi:10.1093/abbs/gmr016. https://pubmed.ncbi.nlm.nih.gov/21444325/

4. Kuang, Jingyu, Duan, Ting, Gao, Changsong, Wang, Wenlun, Zhu, Lingyun. . RNF8 depletion attenuates hepatocellular carcinoma progression by inhibiting epithelial-mesenchymal transition and enhancing drug sensitivity. In Acta biochimica et biophysica Sinica, 55, 661-671. doi:10.3724/abbs.2023076. https://pubmed.ncbi.nlm.nih.gov/37154586/

5. Kuang, Jingyu, Min, Lu, Liu, Chuanyang, Wu, Lei, Zhu, Lingyun. 2020. RNF8 Promotes Epithelial-Mesenchymal Transition in Lung Cancer Cells via Stabilization of Slug. In Molecular cancer research : MCR, 18, 1638-1649. doi:10.1158/1541-7786.MCR-19-1211. https://pubmed.ncbi.nlm.nih.gov/32753472/