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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
Summary
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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