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Fhit Modulates the DNA Damage Checkpoint Response

¹ Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan; ² Institute of Bioregulation, Kyushu University, Ohita, Japan; ³ Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University Comprehensive Cancer Center, Columbus, Ohio; ⁴ Department of Experimental and Clinical Medicine, Medical School of Catanzaro, "Magna Graecia" University of Catanzaro, Catanzaro, Italy; and ⁵ Department of Histopathology, Sant' Andrea Hospital, University of Rome "La Sapienza," Rome, Italy

Requests for reprints: Kay Huebner, Comprehensive Cancer Center, The Ohio State University, 455C Wiseman Hall, 410 West 12th Avenue, Columbus, OH 43210. Phone: 614-292-4850; Fax: 614-292-3312; E-mail: kay.huebner{at}osumc.edu.

In preneoplastic lesions, the DNA damage checkpoint is induced and loss of heterozygosity at the FRA3B/FHIT common chromosome fragile region precedes or is coincident with activation of the checkpoint response in these early stages. Introduction of exogenous Fhit into cells in vitro led to modulation of expression of checkpoint proteins Hus1 and Chk1 at mid-S checkpoint, a modulation that led to induction of apoptosis in esophageal cancer cells but not in noncancerous primary cultures. Mutation of the conserved Fhit tyrosine 114 resulted in failure of this function, confirming the importance of this residue. The results suggest that the DNA damage–susceptible FRA3B/FHIT chromosome fragile region, paradoxically, encodes a protein that is necessary for protecting cells from accumulation of DNA damage through its role in modulation of checkpoint proteins, and inactivation of Fhit contributes to accumulation of abnormal checkpoint phenotypes in cancer development. (Cancer Res 2006; 66(23): 11287-92)

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