Premium
Common variants of Drosophila melanogaster Cyp6d2 cause camptothecin sensitivity and synergize with loss of Brca2
Author(s) -
Thomas Adam Michael,
Hui Carrie,
South Adam,
McVey Mitch
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.760.4
Subject(s) - camptothecin , topotecan , topoisomerase , drosophila melanogaster , biology , irinotecan , genetics , mutation , mutant , genome instability , dna damage , dna repair , dna , gene , cancer , biochemistry , chemotherapy , colorectal cancer
Many chemotherapeutic agents selectively target rapidly dividing cells, including cancer cells, by causing DNA damage that leads to genome instability and cell death. We utilize Drosophila melanogaster to study how mutations in key DNA repair genes affect an organism's response to chemotherapeutic drugs. In this study, we focused on camptothecin and its derivatives, topotecan and irinotecan, which are type I topoisomerase inhibitors that create DNA double strand breaks in rapidly dividing cells. Here, we describe two polymorphisms in Drosophila Cyp6d2 that result in extreme sensitivity to camptothecin, but not topotecan or irinotecan. We confirmed that the sensitivity was due to mutations in Cyp6d2 by rescuing the defect with a wild‐type copy of Cyp6d2. Additionally, we showed that combining a Cyp6d2 mutation with mutations in Drosophila BRCA2 results in extreme sensitivity to camptothecin. Given the frequency of the Cyp6d2 polymorphisms in publicly available Drosophila stocks, our study demonstrates the need for caution when interpreting results from drug sensitivity screens in Drosophila and other model organisms. Furthermore, our findings illustrate how genetic background effects can be important when determining the efficacy of chemotherapeutic agents in various DNA repair mutants.