研究発表を行った学会；オリジナルデータ
タイトル；Differential roles of Rad18 and Chk2 in genome maintenance and skin carcinogenesis following UV exposure.
発表者；田上 友貴氏
（熊本大学 発生医学研究所 損傷修復分野、国際先端生命科学研究推進センター ICALS）
要旨；
Xeroderma pigmentosum variant (XP-V) is an inherited disease, and characterized by increased incidence of skin cancinogenesis at sun-exposed skin areas. The gene responsible for XP-V encodes the DNA polymerase eta (Polη). Polη is controlled by ubiquitin ligase Rad18. However, it is unknown whether the Rad18-deficiency also predisposes pathology of XP-V. Human individuals harboring heterozygous for nonfunctional CHEK2*1100delC that is a SNP of the human CHEK2 gene (orthologue of mouse Chk2), has a 2-fold increased risk of mammalian tumor and malignant melanoma. However, it is unknown whether UV exposure is a risk factor for skin carcinogenesis in humans with dysfunctional CHEK2. This study, we will define the roles of Rad18 and Chk2 in suppressing UV-inducible skin carcinogenesis.
We chronically exposed shaved dorsal skin of WT, Rad18-/-, Chk2-/- and Chk2-/-Rad18-/- mice to UV-B light and observe skin tumorigenesis. We established ES cells and MEFs from each genotypes of mice and evaluated cell survival, cell cycle control, cell death, and frequency of micronucleus formation (an indicator for genomic instability).
The skin cancer formation rate of Rad18-deficient mice was not statistically different from that of WT mice. Chk2-deficient mice developed skin cancers with less dose of UV-B than those of WT mice. UV-irradiated Rad18-deficient ES cells and MEFs were more susceptible to cell cycle arrest at G1/S phase and apoptosis than those of WT cultures. Chk2-deficiency alleviated those phenotypes of both cells, but resulted in increased genomic instability.
It is unlikely that the disfunction of Rad18 leads to pathology of XP-V. The tumor-suppressive role of Polη in UV-treated skin is Rad18-independent. We also define a role for Chk2 in suppressing UV-induced skin carcinogenesis in vivo. This study identifies Chk2 dysfunction as a potential risk factor for sunlight-induced skin tumorigenesis in humans.
