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- W3216007938 abstract "Abstract Resistance to chemotherapy is a leading cause of treatment failure. Drug-resistance mechanisms involve mutations in specific proteins or changes in their expression levels. It is commonly understood that resistance mutations happen randomly prior to treatment and are selected during the treatment. However, selection of drug-resistant mutants in culture could be achieved by multiple drug exposures of cloned genetically identical cells, and thus cannot result from selection of pre-existent mutations. Accordingly, adaptation must involve generation of mutations de-novo upon drug treatment. Here we explored the origin of resistance mutations to a widely used Top1 inhibitor irinotecan, which triggers DNA breaks, causing cytotoxicity. Resistance mechanism involved gradual accumulation of recurrent mutations in non-coding regions of DNA at Top1-cleavage sites. Surprisingly, cancer cells had higher number of such sites than reference genome, which may define their increased sensitivity to irinotecan. Homologous recombination repair of DNA double strand breaks at these sites following initial drug exposures gradually reverted cleavage-sensitive “cancer” sequences back to cleavage-resistant “normal” sequences. These mutations reduced generation of DNA breaks upon subsequent exposures, thus gradually increasing the drug resistance. Together, large target size for mutations and their Top1-guided generation lead to their gradual and rapid accumulation, synergistically accelerating development of resistance. Abstract Figure" @default.
- W3216007938 created "2021-12-06" @default.
- W3216007938 creator A5012954582 @default.
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- W3216007938 creator A5084135451 @default.
- W3216007938 date "2021-11-26" @default.
- W3216007938 modified "2023-10-17" @default.
- W3216007938 title "Homologous recombination repair creates mutations in the non-coding genome that alter Topoisomerase-1 cleavage sites & orchestrates irinotecan resistance" @default.
- W3216007938 cites W1581731557 @default.
- W3216007938 cites W1595957120 @default.
- W3216007938 cites W1894632965 @default.
- W3216007938 cites W1927999720 @default.
- W3216007938 cites W1961709850 @default.
- W3216007938 cites W1987191607 @default.
- W3216007938 cites W1988786503 @default.
- W3216007938 cites W1990085600 @default.
- W3216007938 cites W2007458878 @default.
- W3216007938 cites W2012792853 @default.
- W3216007938 cites W2013955994 @default.
- W3216007938 cites W2014014132 @default.
- W3216007938 cites W2014314802 @default.
- W3216007938 cites W2020642546 @default.
- W3216007938 cites W2038720758 @default.
- W3216007938 cites W2043748488 @default.
- W3216007938 cites W2044197339 @default.
- W3216007938 cites W2046880044 @default.
- W3216007938 cites W2046928699 @default.
- W3216007938 cites W2050361001 @default.
- W3216007938 cites W2050669549 @default.
- W3216007938 cites W2061647035 @default.
- W3216007938 cites W2067951632 @default.
- W3216007938 cites W2069443403 @default.
- W3216007938 cites W2070547493 @default.
- W3216007938 cites W2071735670 @default.
- W3216007938 cites W2072955455 @default.
- W3216007938 cites W2086034451 @default.
- W3216007938 cites W2092629964 @default.
- W3216007938 cites W2096353907 @default.
- W3216007938 cites W2102619694 @default.
- W3216007938 cites W2106578986 @default.
- W3216007938 cites W2108516575 @default.
- W3216007938 cites W2109218147 @default.
- W3216007938 cites W2112814753 @default.
- W3216007938 cites W2128016314 @default.
- W3216007938 cites W2132600317 @default.
- W3216007938 cites W2140650011 @default.
- W3216007938 cites W2150825517 @default.
- W3216007938 cites W2163751095 @default.
- W3216007938 cites W2164617114 @default.
- W3216007938 cites W2168133698 @default.
- W3216007938 cites W2169302611 @default.
- W3216007938 cites W2215790966 @default.
- W3216007938 cites W2268912183 @default.
- W3216007938 cites W2274106006 @default.
- W3216007938 cites W2326269909 @default.
- W3216007938 cites W2414279676 @default.
- W3216007938 cites W2473363865 @default.
- W3216007938 cites W2512058578 @default.
- W3216007938 cites W2530246084 @default.
- W3216007938 cites W2557216615 @default.
- W3216007938 cites W2592982749 @default.
- W3216007938 cites W2616843759 @default.
- W3216007938 cites W2712978371 @default.
- W3216007938 cites W2790768119 @default.
- W3216007938 cites W2791155359 @default.
- W3216007938 cites W2799820269 @default.
- W3216007938 cites W2807001058 @default.
- W3216007938 cites W2829023813 @default.
- W3216007938 cites W2888694031 @default.
- W3216007938 cites W2889194247 @default.
- W3216007938 cites W2914759417 @default.
- W3216007938 cites W2950235057 @default.
- W3216007938 cites W2952527196 @default.
- W3216007938 cites W2967149437 @default.
- W3216007938 cites W2970044521 @default.
- W3216007938 cites W2987148655 @default.
- W3216007938 cites W2990895847 @default.
- W3216007938 cites W3000285141 @default.
- W3216007938 cites W3004884723 @default.
- W3216007938 cites W3005807693 @default.
- W3216007938 cites W3031036292 @default.
- W3216007938 cites W3041813955 @default.
- W3216007938 cites W3086444146 @default.
- W3216007938 cites W3087921738 @default.
- W3216007938 cites W3120627169 @default.
- W3216007938 cites W3124870698 @default.
- W3216007938 cites W3165750568 @default.
- W3216007938 cites W4224306507 @default.
- W3216007938 cites W4232301669 @default.
- W3216007938 cites W4247053599 @default.
- W3216007938 cites W4253216840 @default.
- W3216007938 cites W4254687493 @default.
- W3216007938 doi "https://doi.org/10.1101/2021.11.26.470089" @default.
- W3216007938 hasPublicationYear "2021" @default.