RAD18 transmits DNA damage signalling to elicit homologous recombination repair

• Published in: Nature cell biology Vol. 11; no. 5; pp. 592 - 603
• Main Authors: Huang, Jun, Kim, Hongtae, Yu, Xiaochun, Glover, J N Mark, Leung, Charles Chung Yun, Chen, Junjie, Huen, Michael S. Y
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2009; Nature Publishing Group
• Subjects: Acids; Antibodies; Biomedical and Life Sciences; Camptothecin - pharmacology; Cancer Research; Cell Biology; Cell Line; Cellular signal transduction; Chromatin - metabolism; Deoxyribonucleic acid; Developmental Biology; DNA; DNA - drug effects; DNA - metabolism; DNA - radiation effects; DNA Breaks, Double-Stranded; DNA damage; DNA Damage - physiology; DNA repair; DNA Repair - physiology; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; DNA-Binding Proteins - physiology; Gene Conversion - physiology; Genetic aspects; HeLa Cells; Histones - genetics; Histones - metabolism; Humans; Kinases; Life Sciences; Models, Biological; Physiological aspects; Protein Binding - physiology; Protein Interaction Domains and Motifs - physiology; Proteins; Radiation; Recombination, Genetic - physiology; Signal Transduction - physiology; Stem Cells; Ubiquitin - metabolism; Ubiquitin-Conjugating Enzymes - genetics; Ubiquitin-proteasome system; Ubiquitin-Protein Ligases; Zinc Fingers - physiology; United States; United States > US
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb1865

The ubquitin ligase Rad18 is a central mediator of cell cycle checkpoint activation by DNA damage. Now Rad18 turns out to directly regulate homologous recombination repair by interacting with Rad51C To maintain genome stability, cells respond to DNA damage by activating signalling pathways that govern cell-cycle checkpoints and initiate DNA repair. Cell-cycle checkpoint controls should connect with DNA repair processes, however, exactly how such coordination occurs in vivo is largely unknown. Here we describe a new role for the E3 ligase RAD18 as the integral component in translating the damage response signal to orchestrate homologous recombination repair (HRR). We show that RAD18 promotes homologous recombination in a manner strictly dependent on its ability to be recruited to sites of DNA breaks and that this recruitment relies on a well-defined DNA damage signalling pathway mediated by another E3 ligase, RNF8. We further demonstrate that RAD18 functions as an adaptor to facilitate homologous recombination through direct interaction with the recombinase RAD51C. Together, our data uncovers RAD18 as a key factor that orchestrates HRR through surveillance of the DNA damage signal.