RAD18, an E3 ubiquitin ligase, plays crucial roles in DNA damage tolerance pathways. It is involved in translesion DNA synthesis (TLS) and homologous recombination (HR) repair, preventing replication fork collapse, and maintaining genome stability during DNA replication [1,2,3]. These functions are vital for normal cellular function and the prevention of diseases related to genomic instability.

In human cells, RAD18 can be O-GlcNAcylated at specific residues, which is important for its accumulation at DNA damage sites. Abrogation of this modification limits phosphorylation at Ser434, reducing damage-induced PCNA monoubiquitination, impairing Polη focus formation, and enhancing UV sensitivity. Also, its ubiquitin and RAD51C binding ability at DNA double-strand breaks is O-GlcNAcylation-dependent [1]. In cancer patients, several loss-of-function mutations in RAD18 have been identified, suggesting its involvement in cancer development [2]. In BRCA1-deficient cancer cells, a RAD18-UBC13-PALB2-RNF168 axis promotes fork recovery, and RAD18 is over-expressed in these cancers [5]. In gliomas, RAD18 expression is upregulated, significantly correlated with age, tumor grade, and histological subtype, and patients with high RAD18 expression have worse overall survival [4].

In conclusion, RAD18 is essential for DNA damage repair and genome stability. Studies on RAD18, especially through loss-of-function models in cancer patients and specific cell types, have revealed its significance in cancer development and glioma progression. Understanding RAD18 can potentially offer new strategies for cancer treatment and prevention.

References:

1. Ma, Xiaolu, Fu, Hui, Sun, Chenyi, Tang, Tie-Shan, Guo, Caixia. 2024. RAD18 O-GlcNAcylation promotes translesion DNA synthesis and homologous recombination repair. In Cell death & disease, 15, 321. doi:10.1038/s41419-024-06700-y. https://pubmed.ncbi.nlm.nih.gov/38719812/

2. Palek, Matous, Palkova, Natalie, Kleiblova, Petra, Kleibl, Zdenek, Macurek, Libor. . RAD18 directs DNA double-strand break repair by homologous recombination to post-replicative chromatin. In Nucleic acids research, 52, 7687-7703. doi:10.1093/nar/gkae499. https://pubmed.ncbi.nlm.nih.gov/38884202/

3. Mórocz, Mónika, Qorri, Erda, Pekker, Emese, Tick, Gabriella, Haracska, Lajos. 2023. Exploring RAD18-dependent replication of damaged DNA and discontinuities: A collection of advanced tools. In Journal of biotechnology, 380, 1-19. doi:10.1016/j.jbiotec.2023.12.001. https://pubmed.ncbi.nlm.nih.gov/38072328/

4. Sun, Jiahua, Li, Jun, Lu, Zhengrong, Chen, Lin, Ma, Junfeng. 2022. Analysis of the Mechanism of RAD18 in Glioma. In Neuroimmunomodulation, 29, 327-337. doi:10.1159/000520761. https://pubmed.ncbi.nlm.nih.gov/35367987/

5. Cybulla, Emily, Wallace, Sierra, Meroni, Alice, Zou, Lee, Vindigni, Alessandro. . A RAD18-UBC13-PALB2-RNF168 axis mediates replication fork recovery in BRCA1-deficient cancer cells. In Nucleic acids research, 52, 8861-8879. doi:10.1093/nar/gkae563. https://pubmed.ncbi.nlm.nih.gov/38943334/