TDP 2 modulates the expression of estrogen-responsive oncogenes

Abstract

With its ligand estrogen, the estrogen receptor (ER) stimulates tumor cell growth by activating a global transcriptional program. This activation involves topoisomerase 2 (TOP2), which resolves topological problems by transiently creating and re-ligating DNA double-strand breaks (DSBs). Recent studies have uncovered the involvement of DNA repair proteins in the repair of TOP2-induced DSBs. These noncanonical repair pathways may serve as backup processes when TOP2 is halted and fails to re-ligate DSBs, but their impact on transcription remains elusive. In this study, we investigated the role of tyrosyl-DNA phosphodiesterase 2 (TDP2), an enzyme that acts for the removal of halted TOP2 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 was a very early event (1 hour) and TOP2-dependent. In TDP2-deficient cells, the induction of MYC by estrogen became prolonged and volatile. Bulk and single-cell RNA-seq identified the oncogenes MYC and CCND1 as genes whose estrogen response was regulated by TDP2. These results suggest that TDP2 may play a role in the repair of TOP2-induced DSBs in specific genomic loci and tightly regulates the expression of oncogenes.