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EMBO J January 1, 2022; 41 (12): e110632.
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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 .

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.

PubMed ID: 35578785
Article link: EMBO J
Grant support: [+]

Genes referenced: top2a

References [+] :
Atwal, Intercalating TOP2 Poisons Attenuate Topoisomerase Action at Higher Concentrations. 2019, Pubmed