Molecular parameters of genome instability: roles of fragile genes at common fragile sites

Abstract

Common chromosome fragile sites occur at specific sequences within mammalian genomes that exhibit apparent single-stranded regions in mitotic chromosomes on exposure of cells to replication stress. Recent progress in the characterization of sequences, and more precise mapping of common fragile sites in mammalian and yeast genomes, has led to the exact placement of large common fragile regions straddling the borders of chromosomal G and R bands, with early and late replicating genomic regions, respectively, and could lead to breakthroughs in understanding the function of these evolutionarily conserved but highly recombinogenic chromosome elements. Deficiency of genes involved in DNA damage checkpoint responses, such as ATR, CHK1, HUS1 leads to increased frequency of fragile site instability. Some of these fragile sites, particularly FRA3B, encode genes that are themselves involved in the protection of cells from DNA damage through various mechanisms. Protection of mammalian genomes from accumulation of DNA damage in somatic cells is critical during development, puberty and during the reproductive lifespan, and occurs through mechanisms involving surveillance of the genome for damage, signals to the cell cycle machinery to stop cell cycle progression, signals to repair machinery to repair damage, signals to resume cycling or initiate apoptotic programs, depending on the extent of damage and repair. When genes involved in these processes are altered or deleted, cancer can occur. The tumor suppressor gene, FHIT at the FRA3B locus, and possibly other fragile genes, is a common target of damage and paradoxically encodes a protein with roles in protection from DNA damage.