Differential roles of translesion synthesis polymerases eta and iota in UV-induced mutagenesis of mouse skin cells and tissues.

Authors

Yasutaka Sakurai, Masayuki Yokoi, Taiki Sugimoto, Tsuyoshi Ohkumo, Daiki Morita, Tetsuya Tsukamoto, Tsukasa Oda, Min Gi, Anna Kakehashi, Takayuki Yamashita, Hideki Wanibuchi, Masae Tatematsu, Fumio Hanaoka

Published in

DNA repair. Volume 167. Pages 103974. Oct 28, 2026. Epub Oct 28, 2026.

Abstract

Xeroderma pigmentosum variant (XP-V) is a human genetic disorder characterized by an increased risk of skin cancer following ultraviolet (UV) exposure and caused by a deficiency in DNA polymerase eta (Polη), a specialized enzyme involved in translesion DNA synthesis (TLS). Polι, a paralog of Polη, exhibits TLS activity on UV-induced DNA lesions in vitro; however, its in vivo function remains unclear. We previously reported that Polη- and Polι-deficient mice exposed to UV irradiation developed epithelial and mesenchymal skin tumors, respectively. To elucidate how Polη and Polι suppress UV-induced mutagenesis and tumorigenesis in distinct skin tissues, we analyzed Trp53 mutations in UV-induced skin tumors and established cell lines of mouse epidermal keratinocytes (MKCs) and dermal fibroblasts (MDFs) from wild-type and Polη-deficient mice. Although wild-type MKCs were more resistant to UV irradiation than wild-type MDFs, Polη-deficient MKCs and MDFs exhibited similar UV sensitivity. Polη was rapidly degraded in MDFs following UV irradiation, whereas Polι remained stable. Moreover, Polη deficiency increased the frequency of UV-induced mutations in both MKCs and MDFs; however, this effect was more pronounced in MKCs. Polι knockdown had no substantial effect on UV sensitivity, whereas Polι overexpression reduced the mutation frequency in Polη-deficient MDFs. These findings suggest that Polη and Polι have distinct roles in the UV response and that UV-induced degradation of Polη in MDFs may promote the participation of Polι and alternative polymerases in TLS, thereby contributing to tissue-specific suppression of UV-induced mutagenesis and tumorigenesis.

PMID:
42966327
Bibliographic data and abstract were imported from PubMed on 01 Nov 2026.

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