Aclarubicin disrupts RNA polymerase II progression at replication-coupled histone genes

Authors

Nguyen, K. K., Wooten, M., Ahmad, K., Henikoff, S.

Abstract

Anthracyclines are highly effective chemotherapeutic agents that cause DNA and chromatin damage. One member of the anthracyclines, aclarubicin, has recently gained therapeutic interest due to its ability to kill cancer cells through chromatin-based mechanisms, thus avoiding the off-target effects associated with DNA damage. Despite this, the molecular mechanism of action leading to aclarubicin-induced chromatin damage remains elusive. Here we performed Cleavage Under Targets and Tagmentation (CUT&Tag) of RNA polymerase II (Pol II) and other transcriptional regulators in human cells during aclarubicin treatment. We found that aclarubicin strongly disrupts the replication-coupled histone genes, resulting in a nonproductive accumulation of Pol II-transcription machinery here beyond the levels at other genes. We attribute this sensitivity to the dense Pol II loading and rapid transcription of the histone genes, which intensify the chromatin-disrupting effects of aclarubicin at these loci. Together, our findings support the effectiveness of aclarubicin as an anticancer drug and point to the histone gene cluster as a promising target for therapeutic intervention.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 10 Jul 2026.

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