DNA polymerase theta protects against UV-induced cancer
NIEHS grantees provided evidence that the enzyme DNA polymerase theta (pol Q) protects against skin cancer induced by ultraviolet (UV) light, although pol Q also increases the number of UV-induced mutations. They observed that pol Q might play a protective role through a process called error-prone translesion synthesis (TLS), which allows DNA to replicate past mutations and tolerate DNA damage.
To understand the role of TLS in skin cancer formation, the researchers used cell studies to analyze the enzymes that synthesize DNA molecules, known as DNA polymerases, to determine which DNA polymerase is responsible for generating UV-induced mutations. In cell studies, they showed that pol Q led to an increase in mutations induced by UV exposure and was required to generate certain types of mutations.
Because pol Q led to DNA mutations in cells, the scientists generated a pol Q-deficient mouse model and examined susceptibility to UV-induced skin cancers. Contrary to expectations, the team found that pol Q-deficient mice were more susceptible to skin cancer from UV damage.
The team analyzed the replication of UV-damaged DNA in the mice and discovered that TLS mechanisms by pol Q and other polymerases prevented the collapse of replication forks. Replication forks are active areas of DNA replication that can collapse at sites of DNA damage. This can lead to genomic instability and promote tumor development. Because TLS by pol Q prevented replication fork collapse, the authors suggested that although pol Q can induce mutations, it also provides a safeguard against cancer formation.
Citation: Yoon JH, McArthur MJ, Park J, Basu D, Wakamiya M, Prakash L, Prakash S. 2019. Error-prone replication through UV lesions by DNA polymerase theta protects against skin cancers. Cell 176(6):1295–1309.e15.