Figure 3.

Proposed roles of RAD18 and TLS DNA polymerases in tumorigenesis. Mutagenic TLS of damaged DNA by Y-family DNA polymerases can activate oncogenes (e.g. KRASV12) that initiate carcinogenesis. Oncogene-expressing cells can be eliminated via a DNA damage-mediated senescence program (OIS) that serves as a barrier to tumorigenesis. RAD18/TLS and ATR-CHK1 help sustain damage-tolerant DNA synthesis and viability of cells that breach the OIS barrier. Error-prone TLS might also confer mutability that drives subsequent stages of multi-step tumorigenesis. The selective pressure for cancer cells to activate TLS also confers chemoresistance.