TDP2 is a regulator of estrogen-responsive oncogene expression

Abstract

With its ligand estrogen, the estrogen receptor (ER) initiates a global transcriptional program, promoting cell gro wth. T his process in v olv es topoisomerase 2 (TOP2), a k e y protein in resolving topological issues during transcription b y clea ving a DNA duple x, passing another duple x through the break, and repairing the break. Recent studies re v ealed the in v olv ement of various DNA repair proteins in the repair of TOP2- induced breaks, suggesting potential alternative repair pathways in cases where TOP2 is halted after cleavage. However, the contribution of these proteins in ER-induced transcriptional regulation remains unclear. We in v estigated the role of tyrosyl-DNA phosphodiesterase 2 (TDP2), an enzyme for the removal of halted TOP2 from the DNA ends, in the estrogen-induced transcriptome using both targeted and global transcription analy ses. MYC activ ation b y estrogen, a TOP2-dependent and transient e v ent, became prolonged in the absence of TDP2 in both TDP2-deficient cells and mice. Bulk and single-cell RNA-seq analyses defined MYC and CCND1 as oncogenes whose estrogen response is tightly regulated b y TDP2. T hese results suggest that TDP2 ma y inherently participate in the repair of estrogen-induced breaks at specific genomic loci, e x erting precise control o v er oncogenic gene expression.