Author:
Shiraishi Takeshi,Druck Teresa,Mimori Koshi,Flomenberg Jacob,Berk Lori,Alder Hansjuerg,Miller Webb,Huebner Kay,Croce Carlo M.
Abstract
It has been suggested that delayed DNA replication underlies
fragility at common human fragile sites, but specific sequences
responsible for expression of these inducible fragile sites have not
been identified. One approach to identify such cis-acting sequences
within the large nonexonic regions of fragile sites would be to
identify conserved functional elements within orthologous fragile sites
by interspecies sequence comparison. This study describes a comparison
of orthologous fragile regions, the human
FRA3B/FHIT and the murine
Fra14A2/Fhit locus. We sequenced over
600 kbp of the mouse Fra14A2, covering the region
orthologous to the fragile epicenter of FRA3B, and
determined the Fhit deletion break points in a mouse
kidney cancer cell line (RENCA). The murine Fra14A2
locus, like the human FRA3B, was characterized by a high
AT content. Alignment of the two sequences showed that this fragile
region was stable in evolution despite its susceptibility to mitotic
recombination on inhibition of DNA replication. There were also several
unusual highly conserved regions (HCRs). The positions of predicted
matrix attachment regions (MARs), possibly related to replication
origins, were not conserved. Of known fragile region landmarks, five
cancer cell break points, one viral integration site, and one
aphidicolin break cluster were located within or near HCRs. Thus,
comparison of orthologous fragile regions has identified highly
conserved sequences with possible functional roles in maintenance of
fragility.
Publisher
Proceedings of the National Academy of Sciences
Cited by
57 articles.
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