TDP 2 modulates the expression of estrogen-responsive oncogenes

Manguso, N.; Kim, M.; Joshi, N.; Al Mahmud, R.; Cortes-Ledesma, F.; Cui, X.; Yamada, S.; Ito, J.; Takeda, S.; Giuliano, A. E.; You, S.; Tanaka, H.

doi:10.1101/2022.06.01.494417

bioRxiv · 10.1101/2022.06.01.494417

TDP 2 modulates the expression of estrogen-responsive oncogenes

Manguso, N.·Kim, M.·Joshi, N.·Al Mahmud, R.·Cortes-Ledesma, F.·Cui, X.·Yamada, S.·Ito, J.·Takeda, S.·Giuliano, A. E.·You, S.·Tanaka, H.

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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.

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Manguso, N., Kim, M., Joshi, N., Al Mahmud, R., Cortes-Ledesma, F., Cui, X., Yamada, S., Ito, J., Takeda, S., Giuliano, A. E., You, S., Tanaka, H.. 2022-06-02. TDP 2 modulates the expression of estrogen-responsive oncogenes. https://doi.org/10.1101/2022.06.01.494417

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