title: RAD18 transmits DNA damage signalling to elicit homologous recombination repair.
abstract: 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.
authors.affiliation: Department of Therapeutic Radiology, Yale University School of Medicine, P.O. Box 208040, New Haven, CT 06520, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Huang
authors.forename: Michael S Y
authors.initials: MS
authors.lastname: Huen
authors.forename: Hongtae
authors.initials: H
authors.lastname: Kim
authors.forename: Charles Chung Yun
authors.initials: CC
authors.lastname: Leung
authors.forename: J N Mark
authors.initials: JN
authors.lastname: Glover
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Yu
authors.forename: Junjie
authors.initials: J
authors.lastname: Chen
mesh_terms: D002166:Camptothecin / Q000494:pharmacology; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D004247:DNA / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005785:Gene Conversion / Q000502:physiology; D006367:HeLa Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D011485:Protein Binding / Q000502:physiology; D054730:Protein Interaction Domains and Motifs / Q000502:physiology; D011995:Recombination, Genetic / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics; D044767:Ubiquitin-Protein Ligases; D016335:Zinc Fingers / Q000502:physiology
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; C485954:RAD18 protein, human; C448305:RAD51C protein, human; C486521:RNF8 protein, human; D025801:Ubiquitin; D004247:DNA; C471607:UBE2N protein, human; D044763:Ubiquitin-Conjugating Enzymes; D044767:Ubiquitin-Protein Ligases; D002166:Camptothecin