The molecular basis of fragile sites in human chromosomes

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Abstract

Fragile sites on chromosomes have been classified into a number of groups according to their frequency and the conditions required to induce them. A number of the rare folate-sensitive fragile sites have been characterized and shown to be amplified methylated CCG trinucleotide repeats. One common fragile site has been partly characterized and appears to be a region of fragility, rather than a single site.

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      Several studies have documented that the locus of integration of HPV16 DNA within the human genome is frequently found within common fragile sites (54–56). Although the majority of rare fragile sites in genomic DNA are induced by folate deficiency (57–60), among the common fragile sites, the one at 3p14.2 (FRA3B) (the most sensitive site on normal human chromosomes, which also contains a spontaneous HPV16 integration site (54)) as well as several other common fragile sites can also develop gaps and breaks when DNA replication is perturbed by “folate stress” (involving depletion of cellular deoxynucleotide pools by either folate deficiency or methotrexate) (54, 60–62). Because there is direct evidence for the coincidence of viral integration sites and fragile sites (54), it is possible that HPV16-low folate-organotypic rafts contained integration of HPV16 DNA into these folate-sensitive or “folate-stressed” fragile sites in genomic DNA.

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