Fhit and CHK1 have opposing effects on homologous recombination repair.
Fragile histidine triad (FHIT) gene deletion or promoter methylation and reduced Fhit protein expression occur in approximately 70% of human epithelial tumors and, in some cancers, are clearly associated with tumor progression. Specific Fhit signal pathways have not been identified. We previously reported that compared with Fhit+/+ cells, Fhit-/- cells with an overactivated ATR/CHK1 pathway show increased mutation frequency and resistance to DNA damage-induced killing, indicating that Fhit and the CHK1 pathway have opposing roles in cells responding to DNA damage. In this study, we show that cells, with or without Fhit expression, have similar DNA double-strand break induction levels and similar rejoining rates following ionizing radiation, indicating that the effect of Fhit on cell radiosensitivity is independent of nonhomologous end-joining. By combining I-SceI-induced-DNA double-strand break system and small interfering RNA approach, we also show that knocking down Fhit increases the efficiency of homologous recombination repair of cells, but knocking down Chk1 decreases the efficiency of homologous recombination repair, associated with the sensitivity to ionizing radiation-induced killing. Taken together, the results show that the role of Fhit in affecting the sensitivity of cells to ionizing radiation-induced killing is through the CHK1 pathway linked to homologous recombination repair. These results also illustrate the importance of balanced checkpoint activation in genomic stability and suggest a connection between the radioresistance and mutagenesis, carcinogenesis, as well as tumor progression in Fhit-deficient cells or tissue.
Hu
Baocheng
B
Beijing Institute of Biotechnology, Beijing, China.
Wang
Hongyan
H
Wang
Xiang
X
Lu
Hua-Rui
HR
Huang
Cuifen
C
Powell
Simon N
SN
Huebner
Kay
K
Wang
Ya
Y
D017766:Acid Anhydride Hydrolases / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D000071877:Checkpoint Kinase 1; D004247:DNA / Q000235:genetics / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D051379:Mice; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics*; D011494:Protein Kinases / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D011995:Recombination, Genetic / Q000235:genetics; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D000071877:Checkpoint Kinase 1; D004247:DNA; D009363:Neoplasm Proteins; D011494:Protein Kinases; D034741:RNA, Small Interfering; D000099170:Bis(5'-adenosyl)triphosphatase; C000605867:CHEK1 protein, human; C000605869:Chek1 protein, mouse