Common Fragile Sites Nested at the Interfaces of Early and Late-Replicating Chromosome Bands : Cis Acting Components of the G2/M Checkpoint?

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.

Reduced FHIT Expression Is Associated with Mismatch Repair Deficient and High CpG Island Methylator Phenotype Colorectal Cancer

“…Translational studies have been reported outlining a correlation between FHIT's loss of expression and genomic instability. First, the fact that FHIT is located in a common fragile site on chromosome 3 itself contributes to genomic instability by being prone to chromosomal recombination and changes that mitigate genomic control (Debatisse, El Achkar, and Dutrillaux 2006;Ruiz-Herrera, Castresana, and Robinson 2006). Second, FHIT is a designated tumor suppressor protein that regulates apoptosis and stress responses by interacting with mitochondrial proteins (Pichiorri, Palumbo, et al 2008) and affecting the expression of cell-cycle proteins .…”

Segmental duplications and evolutionary plasticity at tumor chromosome break-prone regions

“…Replication, which starts early in high-CG isochore, pauses for several hours at the transition to low-CG isochore (Schmegner et al 2007). It was proposed that replication disturbance at the transition between these zones may explain "fragility" of certain regions (Debatisse et al 2006). The presence of satellite-rich sequences with a potential to form unusual secondary structures may enhance this instability effect, as it was shown for rare and common fragile sites (Zlotorynski et al 2003;Gericke 2006) and for human rRNA genes (Lebofsky and Bensimon 2005).…”

Common fragile sites and genomic instability

“…The ATR DNA damage checkpoint pathway has been suggested to have an important role in maintaining the stability of CFSs since a deficiency of proteins associated with this pathway, like ATR, BRCA1, and CHK1, results in increased breakages of CFSs (Casper et al, 2002;Durkin et al, 2008). Moreover, CFSs fragility has been associated with late DNA replication (Debatisse et al, 2006) and histone hypoacetylation (Jiang et al, 2009). It has also been hypothesized that, following DNA replication stress CFSs instability derives from prolonged single-stranded regions of unreplicated DNA accumulating at stalled replication forks that escaped the ATR replication checkpoint (Brueckner et al, 2012).…”