Model of possible roles for RAD18 during the S phase and after ICL damage. The E3 ubiquitin ligase activity of RAD18 is required for the ubiquitylation and chromatin loading of FANCD2 and FANCI. RAD18 may modify members of the core complex or other unidentified DNA repair proteins upstream of FANCD2 and FANCI monoubiquitylation and FA pathway activation. RAD18 is also required for ICL repair in steps downstream of FANCD2 and FANCI monoubiquitylation, such as the recruitment of RAD51C in homologous recombinatorial repair through its ZNF domain or possibly the monoubiquitylation of PCNA in TLS.