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Error-Prone Replication through UV Lesions by DNA Polymerase θ Protects against Skin Cancers
Jung-Hoon Yoon1, Mark J McArthur2, Jeseong Park1
1Department of Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, TX 77555, USA.
Abstract:
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.
Insights
Error-prone translesion synthesis (TLS) by Polθ safeguards against skin cancer. Its absence increases cancer incidence, even without typical mutations, highlighting a novel cancer development pathway.
Area of Science:
- Molecular Biology
- Genetics
- Dermatology
Background:
- Sun-exposed skin cancers accumulate driver mutations.
- Translesion synthesis (TLS) is implicated in generating these mutations during UV damage repair.
- The roles of specific DNA polymerases in UV mutagenesis and skin cancer remain unclear.
Purpose of the Study:
- To identify the DNA polymerase responsible for UV-induced mutations.
- To analyze the contributions of error-free Polη and error-prone Polθ to DNA replication and genome stability.
- To investigate the incidence of UV-induced skin cancers in mice deficient for Polθ, Polη, or both.
Main Methods:
- UV damage induction in mouse models.
- Genotyping and analysis of skin cancer incidence.
- Assessment of DNA repair polymerases' roles in mutagenesis.
Main Results:
- Skin cancer incidence increased in Polθ-deficient mice.
- Cancer incidence was further exacerbated in mice lacking both Polθ and Polη.
- These findings suggest Polθ plays a critical role in preventing UV-induced skin cancer.
Conclusions:
- Error-prone TLS by Polθ acts as a safeguard against skin tumorigenesis.
- Cancer formation can occur independently of traditional somatic point mutations.
- Targeting Polθ may offer new strategies for skin cancer prevention.
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