Error-Prone Replication through UV Lesions by DNA Polymerase θ Protects against Skin Cancers

Cancers from sun-exposed skin accumulate “driver” mutations, causally implicated in oncogenesis. Because errors incorporated during translesion synthesis (TLS) opposite UV lesions would generate these mutations, TLS mechanisms are presumed to underlie cancer development. To address the role of TLS in skin cancer formation, we determined which DNA polymerase is responsible for generating UV mutations, analyzed the relative contributions of error-free TLS by Polη and error-prone TLS by Polθ to the replication of UV-damaged DNA and to genome stability, and examined the incidence of UV-induced skin cancers in Polθ^−/−, Polη^−/−, and Polθ^−/− Polη^−/− mice. Our findings that the incidence of skin cancers rises in Polθ^−/− mice and is further exacerbated in Polθ^−/− Polη^−/− mice compared with Polη^−/− mice support the conclusion that error-prone TLS by Polθ provides a safeguard against tumorigenesis and suggest that cancer formation can ensue in the absence of somatic point mutations. Both error-free TLS by DNA polymerase η and error-prone TLS by DNA polymerase θ through UV lesions protect against replication stress-induced chromosomal instability and prevent skin cancer formation.