Fig. 2

IGF-1R and DNA Damage Tolerance. Nuclear IGF-1R phosphorylates PCNA and promotes ubiquitination by RAD18. Ubiquitinated PCNA promotes recruitment of permissive polymerases to ssDNA breaks and stalled replication forks (markers of replication stress). Mono-ubiquitinated PCNA promotes translesion synthesis and error-prone lesion bypass. Poly-ubiquitinated PCNA promotes strand-switching and an error-free lesion bypass mechanism. In either case, the nuclear IGF-1R - PCNA pathway permits stalled replication to proceed allowing cells survival. Unrepaired ssDNA lesions would lead to double-stranded DNA breaks, and cell death. Hence nuclear IGF-1R promotes the survival of tumor cells under replication stress. Created with BioRender.com.