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Induced DNA double strand breaks by genotoxic drugs occur at active transcription H3K36 tri-methylation sites

Ishita Joshi1, Dattatray Sawant1, Jeffrey Ng1

  • 1Department of Biochemistry and Molecular Biology, Upstate Medical University, Syracuse, NY, USA.

Communications Biology
|May 12, 2026
PubMed

Insights

Anti-cancer drugs cause DNA double-strand breaks (DSBs) by creating conflicts between DNA replication and transcription. Active transcription histone marks impede replication forks, leading to DSBs.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • Anti-cancer clastogens induce DNA replication stress, leading to DNA double-strand breaks (DSBs), a major threat to genome integrity.
  • The precise mechanisms by which these chemicals cause DSBs remain incompletely understood.
  • Previous research suggested DSBs occur at transcriptionally active genes, especially those in head-on replication-transcription configurations.

Purpose of the Study:

  • To rigorously test the model that replication stress-induced DSBs arise from replication-transcription conflicts.
  • To investigate the role of active transcription and associated histone marks in DSB formation.
  • To identify specific histone modifications that contribute to DSB susceptibility during replication stress.

Main Methods:

  • Simultaneously mapped the transcriptome and genome-wide DSBs induced by six diverse replication stress inducers.
  • Analyzed the correlation between DSB locations, gene expression, and active transcription histone marks.
  • Investigated the effect of deleting key histone-modifying enzymes (Set2 and Rpd3) on DSB formation.

Main Results:

  • Replication stress-induced DSBs were significantly enriched in genic regions.
  • A positive correlation was observed between DSBs and active transcription histone marks, notably histone H3 lysine 36 tri-methylation (H3K36me3).
  • Deletion of Set2 (H3K36 methyltransferase) markedly reduced camptothecin-induced DSBs, with a lesser reduction observed upon Rpd3 (histone deacetylase) deletion.

Conclusions:

  • Data support a model where DSBs are driven by replication-transcription conflicts induced by replication inhibitors.
  • Active transcription histone markers, particularly H3K36me3, act as impediments to replication fork progression.
  • These histone markers are identified as direct culprits in the etiology of replication stress-induced DSBs.

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