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DNA topoisomerases participate in fragility of the oncogene RET

Dillon, LW and Pierce, LCT and Lehman, CE and Nikiforov, YE and Wang, YH (2013) DNA topoisomerases participate in fragility of the oncogene RET. PLoS ONE, 8 (9).

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Fragile site breakage was previously shown to result in rearrangement of the RET oncogene, resembling the rearrangements found in thyroid cancer. Common fragile sites are specific regions of the genome with a high susceptibility to DNA breakage under conditions that partially inhibit DNA replication, and often coincide with genes deleted, amplified, or rearranged in cancer. While a substantial amount of work has been performed investigating DNA repair and cell cycle checkpoint proteins vital for maintaining stability at fragile sites, little is known about the initial events leading to DNA breakage at these sites. The purpose of this study was to investigate these initial events through the detection of aphidicolin (APH)-induced DNA breakage within the RET oncogene, in which 144 APHinduced DNA breakpoints were mapped on the nucleotide level in human thyroid cells within intron 11 of RET, the breakpoint cluster region found in patients. These breakpoints were located at or near DNA topoisomerase I and/or II predicted cleavage sites, as well as at DNA secondary structural features recognized and preferentially cleaved by DNA topoisomerases I and II. Co-treatment of thyroid cells with APH and the topoisomerase catalytic inhibitors, betulinic acid and merbarone, significantly decreased APH-induced fragile site breakage within RET intron 11 and within the common fragile site FRA3B. These data demonstrate that DNA topoisomerases I and II are involved in initiating APH-induced common fragile site breakage at RET, and may engage the recognition of DNA secondary structures formed during perturbed DNA replication.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Dillon, LW
Pierce, LCT
Lehman, CE
Nikiforov, YEyen1@pitt.eduYEN1
Wang, YH
Date: 11 September 2013
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 8
Number: 9
DOI or Unique Handle: 10.1371/journal.pone.0075741
Schools and Programs: School of Medicine > Pathology
Refereed: Yes
Date Deposited: 17 Oct 2013 15:27
Last Modified: 02 Apr 2021 19:55


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