Figure 4.

Fragile histidine triad gene product (Fhit) and replicative stress. (a) In non‐cancer cells exposed to replication stress and DNA damage, activation of the checkpoint results in the PCNA‐like Hus1/Rad1/Rad9 clamp recognition of damage foci and ATR and Chk1 activation, leading to cell cycle arrest, repair, and survival. In some cells the damage will cause deletion at the FRA3B/FHIT locus and loss of Fhit. In this case, the checkpoint is likely to be aberrant, and cells will accumulate mutations. (b) In Fhit‐deficient cells expressing exogenous Fhit and exposed to severe replication stress, the Chk1 pathway is not appropriately activated, resulting in uncoupling of recognition of DNA damage and activation of Chk1, leading to apoptosis.