Knowledge Bank

Genomic instability is a fascinating hallmark of cancer, important for the accelerated acquisition of cancer-driving mutations. The causes and consequences of genomic instability are not fully understood and have been the subject of intensive investigation by many laboratory groups. The fragile site gene, FHIT, located in locus FRA3B, encodes a protein that demonstrates tumor suppressive functions, is one of the earliest targets mutated in cancer, and has been hypothesized to be a “guardian of the preneoplastic genome” (Pichiorri et al. 2008) To investigate the role of Fhit in promoting genomic integrity, Fhit function was examined in multiple cell lines including cancerous, non-cancerous, and mouse tissue-derived cells. From these studies it was determined that Fhit acts to prevent DNA double-strand breaks (DSBs). Experimental evidence suggests that Fhit utilizes its dinucleoside substrate–binding activity to suppress DSBs, and Fhit mutants with abolished substrate-binding activity fail to minimize DNA breaks. Further study of Fhit positive and negative cells with different types of genotoxic agents suggested that Fhit prevents DNA replication stress, and that replication stress is the source of DNA breaks in Fhit-negative cells. The mechanism(s) through which Fhit participates in this function is still unknown. In experiments in which Chk1, ATR, or ATM were inhibited, each of which are kinases central in the cellular response to replication stress and DSBs, it was found that Fhit and Chk1 functions to prevent DSBs were co-dependent. This functional interaction indicates that Fhit and Chk1 act directly or indirectly within the same pathway during replication stress. From these findings, coupled with the fact that the FHIT gene is one of the earliest and most frequently altered targets in cancer, it is concluded that the loss of Fhit in precancerous cells can therefore contribute to cancer initiation due to the development of DNA breaks and genomic instability. The discovery that the Fhit protein is essential for genome stability is important because it shows that the Fhit loss observed in early preneoplastic lesions underlies the initiation of the genomic instability that is the Hallmark of cancer development and progression. Future experiments designed to understand how Fhit performs this ‘caretaker’ function will allow identification of pathways that may become cancer prevention or therapy targets.