Excessive DNA unwinding in S phase by DNA and RNA polymerases causes topological stress which, if not relieved by topoisomerase II (Topo II), can lead to DNA damage. Investigating why p53-deficient cells are more sensitive to Topo II inhibitors, Yeo et al. showed that treating p53-deficient human and mouse cells with Topo II poisons resulted in higher levels of catalytically inhibited DNA–Topo IIα complexes and of replication-mediated double-strand breaks (DSBs). Notably, inhibition of RNA polymerase II substantially decreased the formation of DNA–Topo IIα complexes and DSBs. Furthermore, even without Topo II inhibition, p53 deficiency impaired replication fork progression, and this was relieved by transcription inhibition. Thus, p53 is important for preventing transcription-induced topological stress that interferes with replication and causes DNA damage.
Yeo, C. Q. et al. p53 maintains genomic stability by preventing interference between transcription and replication. Cell Rep. 15, 132–146 (2016)
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Zlotorynski, E. p53 curbs topological stress. Nat Rev Mol Cell Biol 17, 332 (2016). https://doi.org/10.1038/nrm.2016.70