XB-ART-59122
EMBO J
2022 Jun 14;4112:e110632. doi: 10.15252/embj.2022110632.
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Topoisomerase II poisons inhibit vertebrate DNA replication through distinct mechanisms.
Van Ravenstein SX, Mehta KP, Kavlashvili T, Byl JAW, Zhao R, Osheroff N, Cortez D, Dewar JM.
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Topoisomerase II (TOP2) unlinks chromosomes during vertebrate DNA replication. TOP2 "poisons" are widely used chemotherapeutics that stabilize TOP2 complexes on DNA, leading to cytotoxic DNA breaks. However, it is unclear how these drugs affect DNA replication, which is a major target of TOP2 poisons. Using Xenopus egg extracts, we show that the TOP2 poisons etoposide and doxorubicin both inhibit DNA replication through different mechanisms. Etoposide induces TOP2-dependent DNA breaks and TOP2-dependent fork stalling by trapping TOP2 behind replication forks. In contrast, doxorubicin does not lead to appreciable break formation and instead intercalates into parental DNA to stall replication forks independently of TOP2. In human cells, etoposide stalls forks in a TOP2-dependent manner, while doxorubicin stalls forks independently of TOP2. However, both drugs exhibit TOP2-dependent cytotoxicity. Thus, etoposide and doxorubicin inhibit DNA replication through distinct mechanisms despite shared genetic requirements for cytotoxicity.
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???displayArticle.grants??? [+]
R35 GM128696 NIGMS NIH HHS , R01GM126363 HHS | NIH | National Institute of General Medical Sciences (NIGMS), F32GM136096 HHS | NIH | National Institute of General Medical Sciences (NIGMS), R01CA239161 HHS | NIH | National Cancer Institute (NCI), R01 GM126363 NIGMS NIH HHS , R01 CA239161 NCI NIH HHS , F32 GM136096 NIGMS NIH HHS
Genes referenced: top2a
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