Rnf8, also known as Really Interesting New Gene (RING) Finger Protein 8, is a central factor in DNA double-strand break (DSB) signal transduction [2]. It is involved in multiple biological functions including telomere protection, cell cycle control, and transcriptional regulation, which are closely related to genomic stability [2]. Rnf8, together with the E2 conjugating enzyme UBC13, catalyzes the ubiquitination of histones H2A and H2AX during the DNA damage response (DDR), facilitating the recruitment of downstream DDR factors [3].

Loss of Rnf8 significantly protects Brca1 -mutant mice against mammary tumorigenesis. Rnf8 deficiency in human BRCA1 -mutant breast cancer cells promotes R -loop accumulation and replication fork instability, leading to increased DNA damage, senescence, and synthetic lethality [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 addition, Rnf8 knockdown restrains cell proliferation and alleviates enzalutamide resistance in castration-resistant prostate cancer (CRPC) cells, and Rnf8 depletion attenuates hepatocellular carcinoma (HCC) progression by inhibiting epithelial-mesenchymal transition and enhancing drug sensitivity [4,6]. Rnf8 overexpression impedes glioma stem cell tumorigenicity, and in colon cancer, Rnf8 promotes cancer cell proliferation by inducing β-catenin-mediated c-Myc expression [5,7].

In conclusion, Rnf8 plays a crucial role in DNA damage response, spermatogenesis, and the progression of various cancers including breast, prostate, liver, glioma, and colon cancers. Gene knockout mouse models have been instrumental in revealing these functions, providing insights into the molecular mechanisms underlying disease development and potential therapeutic targets.