Lipid-derived electrophiles mediate the effects of chemotherapeutic topoisomerase I poisons.

ABSTRACT: Topoisomerase 1 (Top1) reversibly nicks chromosomal DNA to relax strain accumulated during transcription, replication, chromatin assembly, and chromosome condensation. The Top1 poison camptothecin targets cancer cells by trapping the enzyme in the covalent complex Top1_cc, tethered to cleaved DNA by a tyrosine-3'-phosphate bond. In vitro mechanistic studies point to interfacial inhibition, where camptothecin binding to the Top1-DNA interface stabilizes Top1_cc. Here we present a complementary covalent mechanism that is critical in vivo. We observed that camptothecins induce oxidative stress, leading to lipid peroxidation, lipid-derived electrophile accumulation, and Top1 poisoning via covalent modification. The electrophile 4-hydroxy-2-nonenal can induce Top1_cc

SUBMITTER: Flor A 

PROVIDER: S-EPMC8206239 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature