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| Status |
Public on Nov 24, 2021 |
| Title |
Evolution of drug resistance in cancer cells involves generation of numerous mutations in non-coding genome that reduces the chances of DNA breaks |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Selection of drug-resistant mammalian cell mutants requires multiple drug exposures. Since cells in starting population could be genetically identical, selection of pre-existent mutations is unlikely. Therefore, adaptation must involve generation of drug-resistant mutations de-novo. Understanding how adaptive mutations are generated and protect cells is important for our knowledge of cancer biology and evolution. Here, we studied adaptation of cancer cells to topoisomerase (Top1) inhibitor irinotecan, which triggers DNA breaks, resulting in cytotoxicity. Resistance mechanism was based on gradual accumulation of recurrent mutations in non-coding DNA at sequence-specific Top1 cleavage sites. Repair of DSBs at these sites following initial irinotecan exposures created mutant sequences that were resistant to further Top1 cleavage. Therefore, by virtue of creating DNA breaks Top1 increases the rate of highly protective mutations specifically at such spots, thus explaining a puzzling need of dose escalation in resistance development.
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| Overall design |
To study the origin of resistance through drug dose adaptation in cancer cells.
PRJNA738674 contains related data with whole genome sequencing of HCT116 cell lines.
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| Contributor(s) |
Kumar S, Gahramanov V, Yagalom J, Patel S, Kaczmarczyk L, Alexandrov I, Gerlitz G, Salmon-Divon M, Sherman M |
| Citation(s) |
37240063 |
| Submission date |
Nov 22, 2021 |
| Last update date |
Aug 10, 2023 |
| Contact name |
Santosh Kumar |
| E-mail(s) |
shashisantosh2007@gmail.com, kumars@ariel.ac.il
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| Phone |
+972559944894
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| Organization name |
Ariel University
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| Department |
Molecular Biology
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| Lab |
Cancer Biology Laboratory
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| Street address |
RamatHa Golan Street 65'
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| City |
Ariel |
| State/province |
Ariel |
| ZIP/Postal code |
40700 |
| Country |
Israel |
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| Platforms (1) |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA782666 |
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