Anthracyclines induce double-strand DNA breaks at active gene promoters

Abstract

Doxorubicin is a widely used chemotherapeutic drug that intercalates between DNA base-pairs and poisons Topoisomerase II, although the mechanistic basis for cell killing remains speculative. Doxorubicin and related anthracycline compounds have been shown to increase nucleosome turnover and/or eviction around promoters, which suggests that the resulting enhanced exposure of DNA might underlie cell killing. Previously, we showed that low doses of anthracyclines increase nucleosome turnover around active gene promoters, which suggests that loss of nucleosomes might contribute to cancer cell killing. Here we apply a genome-wide method to precisely map DNA double-strand breaks (DSBs) in cancer cells. We find that spontaneous DSBs occur preferentially around promoters of active genes, and that both anthracyclines and etoposide, a Topoisomerase II poison, increase DSBs around promoters, although CpG islands are conspicuously protected from DSBs. We propose that torsion-based enhancement of nucleosome turnover by anthracyclines exposes promoter DNA, ultimately causing DSBs around promoters.

Basic fibroblast growth factor promotes doxorubicin resistance in chondrosarcoma cells by affecting XRCC5 expression

“…For the mechanism behind Dox action, many studies have shown that Dox can inhibit topoisomerase II enzyme during DNA replication and subsequently induce DNA double‐strand breaks (DSBs) in cancer cells, leading to cell death . Therefore, enhancement in DNA repair activity of cancer cells would confer resistance to Dox .…”

“…For the mechanism behind Dox action, many studies have shown that Dox can inhibit topoisomerase II enzyme during DNA replication and subsequently induce DNA double-strand breaks (DSBs) in cancer cells, leading to cell death. 47,48 Therefore, enhancement in DNA repair activity of cancer cells would confer resistance to Dox. 38,49,50 Recent studies have indicated that the sensitivity of Dox treatment can be improved by inhibiting the DSB repair pathways, showing leads for novel combination therapies.…”

Genome Organization Drives Chromosome Fragility

“…Such a function has been recently ascribed to TOP1 (Baranello et al, 2016). In contrast, TOP2 activity has been reported to be restricted mainly to promoters of active genes (Baranello et al, 2014; Yang et al, 2015). Thus, it remains unclear how ETO, which specifically poisons TOP2, is linked to oncogenic translocation.…”

“…While TOP2B-induced breaks are enriched at transcriptional start sites (TSS) proportional to the extent of transcription (Baranello et al, 2014; Yang et al, 2015), only a small fraction of genes are affected in TOP2B knockout embryos (McKinnon, 2016). Recent ChIP-seq analysis indicates that TOP2B binding is not confined to promoters, but is generally associated with open chromatin (Uuskula-Reimand et al, 2016).…”

Mechanisms of Nucleosome Dynamics In Vivo

“…Teasing out these interdependencies to understand how ATRX and DAXX mutations can drive ALTor how different H3.3 mutations can drive such different tumors as aggressive DIPGs and benign chondroblastomas requires a better understanding of the dynamic processes that these components normally carry out. Increases in nucleosome dynamics can also result in genome instability, as loss of nucleosomes exposes DNA and can result in double-strand breaks (Yang et al 2015).…”