Excessive MYC-topoisome activity triggers acute DNA damage, MYC degradation, and replacement by a p53-topoisome

Hyperproliferation driven by the protooncogene MYC may lead to tumor suppressor p53 activating DNA damage that has been presumed to derive from hypertranscription and over-replication. Here, we report that excessive MYC-topoisome (MYC/topoisomerase 1/topoisomerase 2) activity acutely damages DNA-activating pATM and p53. In turn, MYC is shut off and degraded, releasing TOP1 and TOP2A from MYC topoisomes in vitro and in vivo. To manage the topological and torsional stress generated at its target genes, p53 assembles a separate topoisome. Because topoisomerase activity is intrinsically DNA damaging, p53 topoisomes provoke an initial burst of DNA damage. Because p53, unlike MYC, upregulates the DNA-damage response (DDR) and activates tyrosyl-DNA-phosphodiesterase (TDP) 1 and TDP2, it suppresses further topoisome-mediated damage. The physical coupling and activation of TOP1 and TOP2 by p53 creates a tool that supports p53-target expression while braking MYC-driven proliferation in mammalian cells. [Display omitted] •Hyperactive MYC topoisome directly and acutely damages DNA•ATM-activating DNA damage triggers the p53 response and MYC degradation•The p53 topoisome (a p53/TOP1/TOP2 complex) increases p53-target-gene expression•p53 and its topoisome, unlike MYC, induce TDP1 and TDP2 to repair topoisomerase-damaged DNA Das et al. use biochemical and genomic methods to show that MYC-topoisome overactivity directly and acutely damages DNA, triggering MYC degradation, p53 induction, and p53-TOP1-TOP2 topoisome formation that, in turn, increases p53-target-gene expression, including TDP1 and TDP2, which help to repair topoisomerase-mediated DNA damage.