DNA Instability at Chromosomal Fragile Sites in Cancer
Pp. 161-188 (28)
Laura W. Dillon, Allison B. Weckerle and Yuh-Hwa Wang
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 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. A recent study of endogenous FRA16C in
human cells showed that replication fork stalling occurs at AT-rich sequences, and
under mild replication stress, the frequency of stalling is increased. 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.
Aphidicolin, ATR pathway, cancer-specific chromosomal translocation,
carcinogenesis, CCDC6, cell-cycle checkpoint protein, chromosomal rearrangement,
DNA damage sensor protein, DNA repair, DNA secondary structure, environmental
mutagen, Fragile Site, genome instability, M-fold, NCOA4, occupational exposure,
papillary thyroid carcinomas, RET, RET/PTC rearrangement, stalled replication
Department of Biochemistry, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1016, USA.