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DNA Damage and Cellular Stress Responses

Components of DNA Damage Checkpoint Pathway Regulate UV Exposure–Dependent Alterations of Gene Expression of FHIT and WWOX at Chromosome Fragile Sites

¹ Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan; ² Institute of Bioregulation, Kyushu University, Ohita, Japan; ³ Department of Pathology, Nagoya University Graduate School of Medicine, Aichi, Japan; and ⁴ Division of Surgical Pathology, University of Rome, La Sapienza, II Faculty of Medicine, Hospital "Santo-Andrea", Rome, Italy

Requests for reprints: Hideshi Ishii, Center for Molecular Medicine, Jichi Medical School, Tochigi 329-0498, Japan. Phone: 81-(02)85-58-7400; Fax: 81-(02)85-44-7501. E-mail: hishii{at}ms.jichi.ac.jp

Common chromosome fragile sites are highly recombinogenic and susceptible to deletions during the development of environmental carcinogen–induced epithelial tumors. Previous studies showed that not only genetic but also epigenetic alterations in cancerous cells are involved in inactivation of the genes FHIT and WWOX at chromosome fragile sites, reported to be potential tumor suppressor genes. Here we investigated the effect of UV light on the gene expression. After exposure to UV, the mRNA and protein of the two genes in murine embryonic fibroblasts (MEF) were unstable, apparently at the G₁-S phase of the cell cycle, which was consistent with nuclear run-on assay. A study of MEFs synchronized via a double thymidine block indicated that, after the exposure, the expression of Fhit and Wwox was reduced in E2f-1–deficient cells and markedly in wild-type cells, whereas the reduction was partially inhibited in Trp53-deficient cells; cells at the S phase seemed to be sensitive to exogenous FHIT, suggesting a role of the checkpoint at the G₁-S phase in the stability of gene expression and a possible involvement of FHIT function at the S phase. The transfection experiment showed that the UV-induced decrease in expression was partially inhibited by transfection of kinase-dead Atr (ataxia telangiectasia mutated and Rad3 related), which is a sensor of UV-induced damage. Taken together, the present study showed that UV-induced alterations of the fragile site gene expression are involved at least partially in the checkpoint function, suggesting the role in the process of carcinogenesis after exposure to UV.

Key Words: chromosome fragile sites

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