Error-prone DNA polymerase θ is required for mutagenic replication through UV-induced DNA lesions.

  • Major finding: Error-prone DNA polymerase θ is required for mutagenic replication through UV-induced DNA lesions.

  • Concept: Cancer incidence increases in Polθ−/− mice due to increased genomic instability caused by stalled replication forks.

  • Impact: Error-prone TLS is protective, and UV-induced tumors can develop in the absence of somatic point mutations.

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There are long-established associations between UV-induced mutation rates and incidences of UV-induced skin cancer, with error-prone replication via translesion synthesis (TLS) thought to be a primary mechanism. To determine the role of TLS in skin cancer formation, Yoon and colleagues assessed the relative contributions of various DNA polymerase (Pol) enzymes and demonstrated that Polθ is indispensable for mutagenic replication through UV-induced cyclobutane pyrimidine dimers and other photoproducts. Depletion of Polθ or Polη reduced the rate of TLS, and combined depletion of both polymerases reduced TLS frequency further, suggesting these polymerases promote TLS via alternate pathways. Similarly, a high incidence of UV-induced mutations followed depletion of the error-free Polη, whereas depletion of the error-prone Polθ reduced mutations to a frequency observed in unirradiated cells. In UV-irradiated human fibroblasts, depletion of Polη, Polθ, or both in combination resulted in reduced progression of DNA replication forks and reduced cell survival. In mouse embryonic fibroblasts, genetic ablation of Polη (Polη−/−), Polϑ (Polϑ−/−), or both (Polϑ−/− Polη−/−) recapitulated these effects and caused increases in single-stranded DNA content, double-strand break (DSB) formation, sister chromatid exchanges, and chromosomal aberrations. Surprisingly, deletion of Polϑ increased the susceptibility of mice to UV-induced skin cancer, and skin tumors in Polϑ−/− Polη−/− mice developed more than twice as quickly as in Polϑ−/− mice and exhibited increased invasive potential and poorer differentiation. Taken together, these data challenge assumptions about UV-induced tumorigenesis and indicate that cancers can readily develop without the contribution of “driver” mutations, with TLS limiting tumorigenesis by preventing the collapse of replication forks stalled at DNA lesions, thereby reducing the incidence of DSBs and subsequent genomic rearrangements.

Yoon J, McArthur MJ, Park J, Basu D, Wakamiya M, Prakash L, et al. Error-prone replication through UV lesions by DNA polymerase ϑ protects against skin cancers. Cell 2019 Feb 14 [Epub ahead of print].

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©2019 American Association for Cancer Research.
2019
American Association for Cancer Research.