Replication timing of two human common fragile sites: FRA1H and FRA2G

  title={Replication timing of two human common fragile sites: FRA1H and FRA2G},
  author={Franca Pelliccia and Nazario Bosco and Angela Curatolo and Angela Rocchi},
  journal={Cytogenetic and Genome Research},
  pages={196 - 200}
The mammalian chromosomes present specific sites of gaps or breaks, the common fragile sites (CFSs), when the cells are exposed to DNA replication stress or to some DNA binding compounds. CFSs span hundreds or thousands of kilobases. The analysis of these sequences has not definitively clarified the causes of their fragility. There is considerable evidence that CFSs are regions of late or slowed replication in the presence of sequence elements that have the propensity to form secondary… 

Figures from this paper

Impaired Replication Timing Promotes Tissue-Specific Expression of Common Fragile Sites
The induction of two CFSs previously found in the human fetal lung fibroblast line are validated in another cell line derived from the same fetal tissue, Institute for Medical Research-90 cells (IMR-90) and the expression of the CFS 1p31.1 and 3q13.3 sites were found to not be fragile in lymphocytes, suggesting a role for epigenetic or transcriptional programs for this tissue specificity.
Secondary structure formation and DNA instability at fragile site FRA16B
It is shown that FRA16B forms an alternative DNA structure in vitro that contributes to its fragility by stalling DNA replication, and this mechanism may be shared among other fragile DNAs.
Mechanisms of Common Fragile Site Instability and Cancer.
Stably transfected common fragile site sequences exhibit instability at ectopic sites and it was found that the integrated FRA3B sequences were not dependent on late replication for their fragility, the first direct evidence in human cells that introduction of CFS sequences into ectopic non-fragile loci is sufficient to recapitulate the instability found at CFSs.
Common Chromosomal Fragile Sites and Cancer
The CFSs exhibit several features characteristic of highly unstable or recombinogenic regions of the genome, and they have been shown to mediate genetic instability in cancers, including during the early stages of tumourigenesis.
Genome-wide high-resolution mapping of mitotic DNA synthesis sites and common fragile sites by direct sequencing
A nucleotide-resolution atlas of MiDAS sites (MDSs) that covered most of the known CFSs, and comprehensively analyzed their sequence characteristics and genomic features, which tallied well with long-standing hypotheses to explain CFS fragility while highlighting the contributions of late replication timing and large transcription units.
Genome Instability at Common Fragile Sites: Searching for the Cause of Their Instability
This review discusses mainly the possible causes that threaten the integrity of CFS in the light of new findings, paying particular attention to the role of the S-phase checkpoint.
Common fragile sites: protection and repair
This work will emphasize the contribution of the structure-prone AT-rich sequences to CFS instability, which is in line with the recent genome-wide study showing that structure-forming repeat sequences are principal sites of replication stress.
A TRF1-controlled common fragile site containing interstitial telomeric sequences
The data show that telomeric DNA is inherently fragile regardless of its genomic position and imply that CFS can be caused by a specific DNA sequence and show 2q14 as the first CFS controlled by a sequence-specific DNA binding protein.
DNA replication stress drives fragile site instability.


Replication of a common fragile site, FRA3B, occurs late in S phase and is delayed further upon induction: implications for the mechanism of fragile site induction.
The studies revealed that FRA3B sequences are late replicating, which supports a model in which common fragile sites are sequences that initiate replication late in S phase or are slow to replicate, and the chromosomal breaks and gaps observed in metaphase cells are due to unreplicated DNA.
Replication Delay along FRA7H, a Common Fragile Site on Human Chromosome 7, Leads to Chromosomal Instability
It is suggested that delayed replication is underlying the fragility at aphidicolin-induced common fragile sites and is enhancing an already existing difference in the replication time along the FRA7H region.
Molecular characterization of the human common fragile site FRA1H
The FRA1H DNA sequence was analyzed to identify coding sequences, the AT content, the type and quantity of the DNA repeats, the CpG islands, the matrix attachment regions, and the number and distribution of high‐flexibility regions and a 120 kb long sequence was identified that may be involved in inducing fragility in the surrounding regions.
Common fragile sites
Findings showing that the key checkpoint genes ATR and BRCA1 are critical for genome stability at fragile sites have shed new light on these mechanisms and on the biological significance of common fragile sites.
The role of late/slow replication of the FRA16D in common fragile site induction
The FRA16D alleles replicate in a synchronous fashion and that replication of these sequences occurs primarily in late S phase extending into G2 phase, supporting a model in which common fragile sites are sequences that may initiate replication in early‐mid S phase but are slow to complete replication, and the chromosomal breaks and gaps observed in metaphase cells result from unreplicated DNA.
Molecular Basis for Expression of Common and Rare Fragile Sites
The results suggest that a shared molecular basis, conferred by sequences with a potential to form secondary structures that can perturb replication, may underlie the fragility of rare fragile sites harboring AT-rich minisatellite repeats and aphidicolin-induced common fragile sites.
Large domains of apparent delayed replication timing associated with triplet repeat expansion at FRAXA and FRAXE.
Study of the replication timing properties of a >2-Mb zone in the FRAXA region (Xq27.3-q28) found the apparent timing of the earlier-replicating allele in female cells in this region was intermediate between normal and affected alleles in males, which is in accordance with expectations of a mixed population of cells resulting from random X inactivation.
Analysis of replication timing at the FRA10B and FRA16B fragile site loci
Analysis of the timing of replication at the FRA10B and FRA16B loci suggests that replication delay may not need to occur at the expanded repeat region itself in order to be permissive for fragility.
A variable domain of delayed replication in FRAXA fragile X chromosomes: X inactivation-like spread of late replication.
This example of variable spreading of late replication into multiple replicons in fragile X provides a model for the spread of inactivation associated with position-effect variegation or X chromosome inactivation.
Characterization of the human common fragile site FRA2G.