Rare fragile sites (RFSs) are classified into two sub-groups based on the compounds that elicit breakage: folate-sensitive groups (for examples, see ), and nonfolate-sensitive groups, which are induced by bromodeoxyuridine (BrdU) or distamycin A, an antibiotic that preferentially binds to AT-pairs of DNA. The folate-sensitive group is characterized by an expansion of CGG repeats, while the nonfolate-sensitive group contains many AT-rich minisatellite repeats.
The instability of CFSs is proposed to stem from late replication: CFSs are likely to initiate proper replication but slow to complete it, introducing breaks from unreplicated regions of DNA. Late-replication may be a result of formation of non-B DNA structures like hairpins and toroids that stall the replication fork in AT rich regions, analogous to the proposed mechanism of rare fragile site instability. Ataxia-telengiectasia and Rad3 Related (ATR) checkpoint kinase is required for maintaining stability of CFS under both stressed and normal replicating conditions. Breakage is reduced after treatment with CPT (camptothecin) (without APH), signifying that CPT also has a necessary role in stabilizing CFSs.
Fragile sites have also been implicated in a variety of syndromes (for a review, see ). For example, breakage at or near the FRA11b locus has been implicated in Jacobsen syndrome, which is characterized by loss of part of the long arm of chromosome 11 accompanied by mild mental retardation. The FRAXE site is associated in the development of a form of mental retardation without any distinctive phenotypic features. Seckel syndrome, a genetic disease characterized by low levels of ATR, results in increased instability of chromosomes at fragile sites.
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