Fig. 5.

Dual role of PCNA-Ub in facilitating FA-mediated ICL repair. ICL repair initiates with the assembly of the FA core complex and ubiquitination of downstream components I-D2, which results in unhooking of the lesion via various endonucleases. When PCNA can be monoubiquitinated at K164 (left), TLS polymerases are actively recruited that can replicate across the unhooked lesion and simultaneously prevent MMR members MSH2-MSH6 from being recruited. This facilitates efficient TLS and downstream repair, resulting in a resolved ICL. In the absence of PCNA-Ub (right), MSH2–MSH6 complex is able to intervene and compete with FA repair. Additionally, inefficient TLS but prevention/delay of HR-repair results in inefficiently resolved ICLs, which amplifies upon MMC exposure. Therefore, PCNA-Ub acts as a molecular balance, that in its ubiquitinated form warrants FA repair and excludes MMR activities. Figure was made with BioRender.com.