Instability at Chromosomal Fragile Sites

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Abstract
Chromosomal fragile sites are loci that are especially prone to forming gaps or breaks on metaphase chromosomes when cells are cultured under conditions that inhibit DNA replication or repair. The relationship of “rare” folate sensitive fragile sites with (CCG)n expansion and, in some cases, genetic disease is well established. Although they comprise the vast majority of fragile sites, much less is known at the molecular level about the “common” fragile sites. These fragile sites may be seen on all chromosomes as a constant feature. In addition to forming fragile sites on metaphase chromosomes, they have been shown to display a number of characteristics of unstable and highly recombinogenic DNA in vitro, including chromosome rearrangements, sister chromatid exchanges and, more recently, intrachromosomal gene amplification. Only one such fragile site, FRA3B at 3p14.2, has been extensively investigated at the molecular level. It extends over a broad region of possibly 500 kb, and no trinucleotide or other simple repeat motifs have been identified in the region. FRA3B has recently been shown to lie within the FHIT gene locus. This region and the FHIT gene are unstable in a number of tumors and tumor cell lines. It thus appears that common fragile sites are also associated with unstable regions of DNA in vivo, at least in some tumor cells, and may cause this instability. Current challenges include determining the mechanism of fragile site expression and instability, and both the environmental and genetic factors that influence this process. Candidate factors include those genes involved in DNA repair and cell cycle and common carcinogens such as those in cigarette smoke.