Topoisomerase-I- and Alu-mediated genomic deletions of the APC gene in familial adenomatous polyposis
Germline mutation in the adenomatous polyposis coli (APC) gene results in familial adenomatous polyposis (FAP), a heritable form of colorectal cancer. We have previously reported two novel mutations that delete exons 11 and 14 of the APC gene, respectively, at the cDNA level without any splice junction defects at the genomic level. We describe here the precise breakpoints of the two mutations and the possible mechanisms leading to the genomic rearrangement. The first rearrangement is most likely a topoisomerase-I-mediated non-homologous recombination resulting in a 2-kb deletion that deletes exon 11 of the APC gene. Both 5' and 3' breakpoints have two topoisomerase I recognition sites and runs of pyrimidines within the 10-bp sequences in their vicinity. Further, the 3' breakpoint has an adenine-thymidine-rich region. This is probably the first report of a topoisomerase-I-mediated germline mutation in a tumor suppressor gene. The second rearrangement is most likely an Alu-Alu homologous recombination resulting in a 6-kb deletion encompassing exon 14. The Alu elements at the 5' and 3' breakpoints include the 26-bp core sequence thought to stimulate recombination. In both rearrangements, partial sequences from the long interspersed nuclear element family are in the vicinity of the breakpoints. Other than serving as markers for regions of DNA damage, their precise role in the recombination events, if any, is unclear. Both deletions result in truncated APC proteins missing the β-catenin- and axin-binding domains, resulting in severe polyposis and cancer.
KeywordsGermline Mutation Familial Adenomatous Polyposis Adenomatous Polyposis Coli Splice Junction Genomic Deletion
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