Abstract
Human chromosomal fragile sites are specific genomic regions which exhibit gaps or breaks on metaphase chromosomes following conditions of partial replication stress. Fragile sites often coincide with genes that are frequently rearranged or deleted in human cancers, with over half of cancer-specific translocations containing breakpoints within fragile sites. But until recently, little direct evidence existed linking fragile site breakage to the formation of cancer-causing chromosomal aberrations. Studies have revealed that DNA breakage at fragile sites can induce formation of RET/PTC rearrangements, and deletions within the FHIT gene, resembling those observed in human tumors. These findings demonstrate the important role of fragile sites in cancer development, suggesting that a better understanding of the molecular basis of fragile site instability is crucial to insights in carcinogenesis. It is hypothesized that under conditions of replication stress, stable secondary structures form at fragile sites and stall replication fork progress, ultimately resulting in DNA breaks. A recent study examining an FRA16B fragment confirmed the formation of secondary structure and DNA polymerase stalling within this sequence in vitro, as well as reduced replication efficiency and increased instability in human cells. Polymerase stalling during synthesis of FRA16D has also been demonstrated. The ATR DNA damage checkpoint pathway plays a critical role in maintaining stability at fragile sites. Recent findings have confirmed binding of the ATR protein to three regions of FRA3B under conditions of mild replication stress. This review will discuss recent advances made in understanding the role and mechanism of fragile sites in cancer development.
Highlights
Genomic instability is a common cause of chromosomal aberrations in many types of tumor cells
Chromosomal fragile sites, which are especially susceptible to DNA breakage, have been suggested as contributory to the formation of cancer-specific chromosomal aberrations [2]
In a recent study by Gandhi et al, DNA breakage at fragile sites directly contributed to the formation of a cancerspecific chromosomal translocation found in human papillary thyroid carcinoma [8]
Summary
Genomic instability is a common cause of chromosomal aberrations in many types of tumor cells. A consensus sequence has not yet been identified among all fragile sites, all common fragile DNAs examined to date are comprised of AT-rich flexibility islands, with the potential of forming secondary structures that are much more stable than other genomic regions [15, 16]. It is hypothesized that at fragile sites, under conditions of replication stress, the replicative polymerases may uncouple from the helicase, resulting in long regions of single-stranded DNA and promoting the formation of stable secondary structures. These structures may stall replication fork progression, triggering. We will discuss the importance of fragile sites, direct evidence of their involvement in cancer, sequence characteristics of fragile sites that contribute to their instability, and the role of the ATR-dependent DNA damage checkpoint pathway in their breakage
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