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Intrachromosomal Gene Amplification Triggered by Hairpin-Capped Breaks Requires Homologous Recombination and is Independent of Nonhomologous End-Joining

Vidhya Narayanan and Kirill S. Lobachev

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Gene amplification is one of the major mechanisms of acquisition of drug resistance and activation of oncogenes in tumors. In mammalian cells, amplified chromosomal regions are manifested cytogenetically as extrachromosomal double minutes (DMs) and chromosomal homogeneously staining regions (HSRs). We recently demonstrated using yeast model system that hairpin-capped double strand breaks (DSBs) generated at the location of human Alu-quasipalindromes can trigger both types of gene amplification. Specifically, the dicentric chromosomes arising from replication of hairpin-capped molecules can be precursors for intrachromosomal amplicons. The formation of HSRs can be accounted for either by breakage-fusion-bridge (BFB) cycle which necessitates nonhomologous end-joining pathway (NHEJ) or by the repair event involving homologous recombination (HR). In this study, we report that intrachromosomal gene amplification mediated by hairpin-capped DSBs is independent of NHEJ machinery, however requires the functions of Rad52 and Rad51 proteins. Based on our observations, we propose a HR-dependent mechanism to explain how the breakage of dicentric chromosomes can lead to the formation of HSRs.

Authors

Vidhya Narayanan

Georgia Institute of Technology; Atlanta, GA USA

Kirill S. Lobachev

Georgia Institute of Technology; Atlanta, GA USA

Purchase article for $19

Subscribe to this journal for $129/year