Doxorubicin, a DNA intercalator, inhibits transcription elongation

Abstract

Doxorubicin is a chemotherapeutic drug for cancer that intercalates into nucleosome-free regions at promoters. Doxorubicin was reported to result in loss of histone H3 trimethylated lysine 4 (H3K4me3). To further explore doxorubicin's mechanism of action, we determined the genomic location of the binding sites of doxorubicin in leukemic cells. The effect of doxorubicin intercalation into the chromatin of leukemic cells on histone modifications was also determined. We show that doxorubicin binding sites were present in the nucleosome-free regions associated with regulatory regions (promoters, enhancers, and super-enhancers) and in the gene body (introns). Doxorubicin treatment did not alter the levels of H3K4me3 and many other histone modifications but significantly lowered H2B ubiquitinated at lysine 120 (H2BK120ub), an elongation-dependent modification. Lastly, we demonstrate that doxorubicin results in the degradation of the largest subunit (RPB1) of RNA polymerase II.

Keywords: H2B ubiquitination; RNA polymerase II degradation; doxorubicin; elongation; leukemia.