Fragile site orthologs FHIT/FRA3B and Fhit/Fra14A2: Evolutionarily conserved but highly recombinogenic

Abstract

Common fragile sites are regions that show elevated susceptibility to DNA damage, leading to alterations that can contribute to cancer development. FRA3B, located at chromosome region 3p14.2, is the most frequently expressed human common fragile site, and allelic losses at FRA3B have been observed in many types of cancer. The FHIT gene, encompassing the FRA3B region, is a tumor-suppressor gene. To identify the features of FHIT/FRA3B that might contribute to fragility, sequences of the human FHIT and the flanking PTPRG gene were compared with those of murine Fhit and Ptprg. Human and mouse orthologous genes, FHIT and Fhit, are more highly conserved through evolution than PTPRG/Ptprg and yet contain more sequence elements that are exquisitely sensitive to genomic rearrangements, such as high-flexibility regions and long interspersed nuclear element 1s, suggesting that common fragile sites serve a function. The conserved AT-rich high-flexibility regions are the most characteristic of common fragile sites.