Fig.4.

FAN1 at the cross-road of genome maintenance pathways. (a) FAN1 promotes FA pathway-independent repair of ICLs. FAN1 catalyzes ICL unhooking by endo-nucleolytic incision followed by exo-nucleolytic digestion of DNA past the lesion, thereby generating a substrate for TLS polymerases (ICLs are indicated by red box). (b) FAN1 interacts with MutLα and may function as a compensatory nuclease in MMR in the absence of EXO1. (c) FAN1 promotes PCNA mono-ubiquitylation on the K164 residue. Further modification of the same residue via K63-linked polyubiquitination is then required for the recruitment of the ZRANB3 translocase and fork reversal, an error-free damage tolerance pathway. (d) FAN1 binds ubiquitylated PCNA on K164 and activates a feed forward loop that enhances PCNA ubiquitylation and possibly TLS (aberrant DNA lesions are indicated by open triangles).