Rad18-dependent SUMOylation of human specialized DNA polymerase eta is required to prevent under-replicated DNA

Translesion polymerase eta (polZ) was characterized for its ability to replicate ultraviolet-induced DNA lesions that stall replicative polymerases, a process promoted by Rad18-dependent PCNA mono-ubiquitination. Recent findings have shown that polZ also acts at intrinsically difficult to replicate sequences. However, the molecular mechanisms that regulate its access to these loci remain elusive. Here, we uncover that polZ travels with replication forks during unchallenged S phase and this requires its SUMOylation on K163. Abrogation of polZ SUMOylation results in replication defects in response to mild replication stress, leading to chromosome fragments in mitosis and damage transmission to daughter cells. Rad18 plays a pivotal role, independently of its ubiquitin ligase activity, acting as a molecular bridge between polZ and the PIAS1 SUMO ligase to promote polZ SUMOylation. Our results provide the first evidence that SUMOylation represents a new way to target polZ to replication forks, independent of the Rad18-mediated PCNA ubiquitination, thereby preventing under-replicated DNA.