Common fragile sites (CFSs) are large chromosomal regions identified by conventional cytogenetics as sequences prone to breakage in cells subjected to replication stress. The interest in CFSs stems from their key role in DNA damage, resulting in chromosomal rearrangements. The instability of CFSs was correlated with genome instability in precancerous lesions and during tumor progression. Two opposing views dominate the discussion regarding the role of CFSs. One school of thought suggested that genomic instability during cancer progression causes collateral damage to genes residing within CFSs, such as WWOX and FHIT. These genes are proposed to be unselected ‘‘passenger’’ mutations. The counter argument is that deletions and other genomic alterations in CFSs occur early in cancer development. Cancer cells with deletions in genes that span CFSs are then selectively expanded due to loss of tumor suppressor functions such as protection of genome stability, coordination of cell cycle or apoptosis. We have recently proposed another model by which these two viewpoints of CFS function are not mutually exclusive but rather coexist; when breaks at CFSs are not repaired accurately, this can lead to deletions by which cells acquire growth advantage because of loss of tumor suppressor activities (Hazan et. al. Plos Genetics, 2016).
Further investigation clearly suggest that gene products from CFSs play important roles in other human diseases. For example, we have evidence for the involvement of DNA damage and WWOX in neurological disease, particularly in childhood epilepsy.
Our project aims to investigate the role of tumor suppressor gene products (TSGPs) of CFSs in human diseases, particularly in cancer, metabolic and in neurological diseases. Three approaches were taken to tackle this question. First, molecular functions of TSGPs of CFSs in several cancer cells was determined using state-of-the-art genetic tools in vitro. Second, novel transgenic mouse tools were used to study CFSs and their associated TSGs in preneoplastic lesions and tumors in vivo, with confirmatory studies in human material. Third, discover potential involvement of CFSs and their TSGPs in metabolic diseases as well as in childhood epilepsy models and systems.
