Differential Roles of Rad18 and Chk2 in Genome Maintenance and Skin Carcinogenesis Following UV Exposure.

Abstract

Defects in DNA polymerase Eta (Polη) cause the sunlight-sensitivity and skin cancer-propensity disorder xeroderma pigmentosum variant. The extent to which Polη function depends on the upstream E3 ubiquitin ligase Rad18 is controversial and has not been investigated using mouse models. Therefore, we tested the role of Rad18 in UV-inducible skin tumorigenesis. Because Rad18 deficiency leads to compensatory DNA damage signaling by Chk2, we also investigated genetic interactions between Rad18 and Chk2 in vivo. Chk2-/-Rad18-/- mice were prone to spontaneous lymphomagenesis. Both Chk2-/- and Chk2-/-Rad18-/- mice were prone to UV-B irradiation-induced skin tumorigenesis when compared with wild-type (WT) animals, but unexpectedly Rad18-/- mice did not recapitulate the skin tumor propensity of Polη mutants. UV-irradiated Rad18-/- cells were more susceptible to G1/S arrest and apoptosis than WT cultures. Chk2 deficiency alleviated both UV-induced G1/S phase arrest and apoptosis of WT and Rad18-/- cells, but led to increased genomic instability. Taken together, our results demonstrate that 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.

• Authors: Yuki Tanoue, Takeshi Toyoda, Jinghua Sun, Md Kawsar Mustofa, Chie Tateishi, Shinya Endo, Noboru Motoyama, Kimi Araki, Di Wu, Yutaka Okuno, Tetsuya Tsukamoto, Motohiro Takeya, Hironobu Ihn, Cyrus Vaziri, Satoshi Tateishi
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 138 Issue 12 Pg. 2550-2557 (12 2018) ISSN: 1523-1747 [Electronic] United States
• PMID: 29859927 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• DNA-Binding Proteins
• Rad18 protein, mouse
• Checkpoint Kinase 2
• Chek2 protein, mouse
• DNA-Directed DNA Polymerase
• Rad30 protein

Topics

• Animals
• Apoptosis
• Carcinogenesis
• Cell Cycle Checkpoints
• Cells, Cultured
• Checkpoint Kinase 2 (genetics, metabolism)
• DNA-Binding Proteins (genetics, metabolism)
• DNA-Directed DNA Polymerase (genetics)
• Fibroblasts (physiology)
• Genomic Instability
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mutation (genetics)
• Neoplasms, Radiation-Induced (genetics, metabolism)
• Skin (pathology, radiation effects)
• Skin Neoplasms (genetics, metabolism)
• Ultraviolet Rays (adverse effects)