Abstract
Genetic analysis has strongly implicated human FHIT (Fragile Histidine Triad) as a tumor suppressor gene, being mutated in a large proportion of early‐stage cancers. The functions of the FHIT protein have, however, remained elusive. Here, we investigated aph1 +, the fission yeast homolog of FHIT, for functions related to checkpoint control and oxidative metabolism. In sublethal concentrations of DNA damaging agents, aph1Δ mutants grew with a substantially shorter lag phase. In aph1Δ mutants carrying a hypomorphic allele of cds1 (the fission yeast homolog of Chk2), in addition, increased chromosome fragmentation and missegregation were found. We also found that under hypoxia or impaired electron transport function, the Aph1 protein level was strongly depressed. Previously, FHIT has been linked to regulation of the human 9‐1‐1 checkpoint complex constituted by Hus1, Rad1, and Rad9. In Schizosaccharomyces pombe, the levels of all three 9‐1‐1 proteins are all downregulated by hypoxia in similarity with Aph1. Moreover, deletion of the aph1 + gene reduced the Rad1 protein level, indicating a direct relationship between these two proteins. We conclude that the fission yeast FHIT homolog has a role in modulating DNA damage checkpoint function, possibly through an effect on the 9‐1‐1 complex, and that this effect may be critical under conditions of limiting oxidative metabolism and reoxygenation.
Highlights
Inactivation of FHIT, through deletion, point mutation, or DNA methylation, is a very common event in cancer
We conclude that the fission yeast FHIT homolog has a role in modulating DNA damage checkpoint function, possibly through an effect on the 9‐1‐1 complex, and that this effect may be critical under conditions of limiting oxidative metabolism and reoxygenation
We have shown that aph1Δ mutants restart growth from the stationary phase at a much earlier point when exposed to various genotoxic agents (PL, HU, and Dox) than wt (Figures 1B–D), indicating that elimination of Aph1 results in unresponsiveness to checkpoint control
Summary
Inactivation of FHIT, through deletion, point mutation, or DNA methylation, is a very common event in cancer. It occurs in over half of human cancers, in particular in epithelial tumors, of which 70% suffer this impairment (Huebner and Croce, 2001; Saldivar et al, 2011). Because of the location at a fragile site, it was initially questioned if FHIT was a true tumor suppressor or just frequently altered. The current view is that FHIT, due to its location on a fragile site, is prone to break in replication stress, and that its loss leads to more replication stress as well as to incompetence in appropriately handling new damage (Saldivar et al, 2012). This, in turn, leads to further progression of cancer development
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