A p53-topoisome replaces the acutely genotoxic MYC- topoisome to empower DNA-damage repair in cells
Hyperproliferation driven by the protooncogene MYC has been presumed to elicit a chain of event that leads to DNA damage and activates the tumor suppressor p53 response. This DNA damage has been presumed to derive from hypertranscription and overreplication. Here, we report that MYC-topoisome (MYC/Topoisomerase 1/Topoisomerase 2) formation is genotoxic within minutes of its formation. Topoisome mediated damage activates pATM and p53, that in turn shuts off MYC and dissociates the topoisome in vitro and in vivo. To manage topological and torsional stress generated at its targets, p53 assembles its own topoisome. Because topoisomerase activity is intrinsically DNA-damaging, the p53-topoisome creates initial burst of DNA damage but, because p53 (unlike MYC) upregulates the DNA damage response and activates TDP1 and TDP2, this damage is quickly suppressed. The novel coupling of TOP1 and TOP2 sponsored by p53, creates a tool to support the expression of p53 targets while braking MYC-accelerated cell growth. Overall design: To pull down the "topisome" complex we designed cross CAD-seq method which involves trapping of TOP2A by etoposide treatment and then proceeding with a pull down against TOP1. TOP1cc cross-CAD-seq was performed in HO15.19 MYC-ER cells with and without p53 induction by nutlin to look at the formation of the p53-topisome.