Late replication and chromosome fragility.

Common fragile sites (CFSs) (n <100) are specific regions in human chromosomes that are particularly liable to show gaps or breaks when the cells are exposed to DNA replication stress or to some DNA binding compounds (Sutherland et al., 1998) (Fig. 1). They are important sites of chromosomal instability that extend for hundreds or thousands of kbs and are preferentially involved in events such as chromosome rearrangements, recombinations, sister chromatid exchanges or viral integrations. Moreover CFSs coincide with breakpoints of recurrent chromosome mutations and gene amplifications in cancer cells. All analyzed individuals present CFSs. The analysis of the sequences of 22 CFSs characterized molecularly has not definitively clarified the causes of their fragility. Considerable evidence supports the opinion that CFSs are regions of late or slowed replication caused by stalling of replication forks due to sequence elements that form secondary structures (Fig. 2). Most of the CFSs cloned to date contain higher numbers of flexible sequences than the non-fragile regions; these sequences are rich in AT-dinucleotide runs that have the potential to form secondary structures and therefore to affect the replication (Zlotorynski et al., 2003). It is now common opinion that the expression of CFSs as chromosome gaps or breaks may be due to unreplicated DNA.