TDP 2 modulates the expression of estrogen-responsive oncogenes

Estrogen receptor (ER) is the most prevalent marker of breast cancer. With its ligand estrogen, ER stimulates tumor cell growth by activating a global transcriptional program. The activation involves topoisomerase 2 (TOP2), which resolves topological problems during transcription by transiently creating and re-ligating DNA double-strand breaks (DSBs). Recent studies revealed that other DNA repair proteins also participate in the repair of TOP2-induced DSBs. These noncanonical repair pathways could act as backup processes when TOP2 fails to re-ligate DSBs, but their definite roles remain elusive. Here we examined the role of tyrosyl-DNA phosphodiesterase 2 (TDP2), an enzyme that promotes the removal of abortive TOP2 complex from the 5’-end of the DNA, in the estrogen-induced transcriptome. Using TDP2-deficient ER-positive cells and mice, we showed that TDP2 regulates the expression of oncogene MYC. MYC induction by estrogen is a very early (1 hour) and TOP2-dependent event. Without TDP2, the induction of MYC by estrogen became prolonged and volatile at a later time point. Bulk and single-cell RNA-seq identified oncogenes MYC and CCND1 as genes in which estrogen response was regulated by TDP2. These results could imply that TDP2 plays a role in the repair of TOP2-induced DSBs in specific genomic loci and tightly regulates oncogenic gene expression.

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