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. 2009 Jun 10;4(6):e5859. doi: 10.1371/journal.pone.0005859

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Muslimović et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.

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A homodimer of topoII binds and cleaves cellular DNA, generating a topoII-linked DSB. Etoposide binds independently to each monomer to block religation, locking the topoII monomer to the DNA break. If only one of the topoII monomers is bound by etoposide and unable to religate the break, this results in a topoII-linked SSB (a). When both monomers are occupied by etoposide, a topoII-linked DSB will be stabilized (b). TopoII-linked DNA breaks that are encountered by RNA or DNA polymerases during etoposide exposure will be denatured and therefore unable to religate the breaks. Denatured topoII will be cleared from the breaks, resulting in free DSBs that can induce H2AX phosphorylation. The relative amounts of these breaks as a percentage of all etoposide-induced breaks are indicated.