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Updated: Jun 28, 2025

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TDP2 is a regulator of estrogen-responsive oncogene expression

Nicholas Manguso1, Minhyung Kim2, Neeraj Joshi1

  • 1Department of Surgery, Cedars-Sinai Medical Center, West Hollywood, CA 90048 USA.

NAR Cancer
|April 10, 2024
PubMed

Insights

Tyrosyl-DNA phosphodiesterase 2 (TDP2) regulates estrogen-induced gene expression. In TDP2-deficient cells, estrogen-driven oncogene activation, like MYC, is prolonged, suggesting TDP2

Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • Estrogen receptor (ER) signaling promotes cell growth via transcriptional regulation.
  • Topoisomerase 2 (TOP2) is crucial for transcription but can induce DNA breaks.
  • The role of DNA repair proteins in ER-mediated transcription is not fully understood.

Purpose of the Study:

  • To investigate the function of tyrosyl-DNA phosphodiesterase 2 (TDP2) in estrogen-induced transcription.
  • To determine TDP2's role in regulating oncogene expression, such as MYC and CCND1, in response to estrogen.

Main Methods:

  • Targeted and global transcription analyses were employed.
  • Studies utilized TDP2-deficient cells and mice.
  • Bulk and single-cell RNA sequencing (RNA-seq) were performed.

Main Results:

  • Estrogen-induced MYC activation, normally transient and TOP2-dependent, was prolonged in the absence of TDP2.
  • TDP2 deficiency led to sustained MYC and CCND1 expression in response to estrogen.
  • RNA-seq analyses confirmed MYC and CCND1 as key oncogenes regulated by TDP2 during estrogen signaling.

Conclusions:

  • TDP2 plays a critical role in the repair of estrogen-induced DNA breaks at specific genomic sites.
  • TDP2 precisely controls the expression of oncogenes like MYC and CCND1 in response to estrogen.
  • TDP2 acts as a regulator of the estrogen-induced transcriptome, impacting cell growth and oncogenesis.

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