Common fragile sites nested at the interfaces of early and late-replicating chromosome bands

Abstract

Common fragile sites (CFS) are evolutionary conserved loci where damage appears recurrently upon treatments perturbing DNA synthesis. Although long studied, the mechanisms underlying CFS fragility are still incompletely understood and CFS function is unknown. We have mapped most of them at the junction of chromosomal bands replicating at different times in S phase, indicating that specific replication programs take place at CFS. In good agreement with this finding, we obtained results suggesting that CFS remain incompletely replicated up to late G(2), even in cells that went unperturbed through S phase. The recent demonstration that the function of ATR and its downstream targets are crucial to CFS stability may thereby indicate that mitotic onset is delayed until completion of their replication. Altogether, available results now suggest that CFS constitute integral "cis" components of the G(2)-M checkpoint.