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<p>Many anti-cancer clastogens are known to induce DNA replication stress and ultimately DNA double-strand breaks (DSBs), one of the most deleterious forms of DNA damage and threat to genome integrity. However, the mechanism(s) by which these chemicals cause DSB is unclear. Our previous work suggested that they induce DSB at transcriptionally up-regulated genes, particularly those oriented in a head-on configuration with respect to incoming replication. Here, we rigorously test this model by simultaneously mapping the transcriptome and genome-wide DSBs induced by six replication stress induders with diverse mechanisms of action (hydroxyurea, methyl-methane sulfonate, camptothecin, actinomycin, doxorubicin and methotrexate). Our data show that replication stress-induced DSBs are enriched in genic regions and show a positive correlation with active transcription histone marks, particularly histone H3 lysine 36 tri-methylation. We further demonstrated that camptothecin-induced DSBs were significantly reduced by deletion of Set2, the known H3K36 methyltransferase, and to a lesser extent, by deletion of Rpd3, a histone deacetylase recognizing H3K36 trimethylation. Our data provide support for a model where DSBs are driven by replication inhibitor-induced replication-transcription conflict. More importantly, they reveal active transcription histone markers as the impediments for replication fork progression, therefore a direct culprit for DSBs.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月12日

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  • Ishita Joshi,
  • Dattatray Sawant,
  • Jeffrey Ng,
  • Wenyi Feng

摘要

Many anti-cancer clastogens are known to induce DNA replication stress and ultimately DNA double-strand breaks (DSBs), one of the most deleterious forms of DNA damage and threat to genome integrity. However, the mechanism(s) by which these chemicals cause DSB is unclear. Our previous work suggested that they induce DSB at transcriptionally up-regulated genes, particularly those oriented in a head-on configuration with respect to incoming replication. Here, we rigorously test this model by simultaneously mapping the transcriptome and genome-wide DSBs induced by six replication stress induders with diverse mechanisms of action (hydroxyurea, methyl-methane sulfonate, camptothecin, actinomycin, doxorubicin and methotrexate). Our data show that replication stress-induced DSBs are enriched in genic regions and show a positive correlation with active transcription histone marks, particularly histone H3 lysine 36 tri-methylation. We further demonstrated that camptothecin-induced DSBs were significantly reduced by deletion of Set2, the known H3K36 methyltransferase, and to a lesser extent, by deletion of Rpd3, a histone deacetylase recognizing H3K36 trimethylation. Our data provide support for a model where DSBs are driven by replication inhibitor-induced replication-transcription conflict. More importantly, they reveal active transcription histone markers as the impediments for replication fork progression, therefore a direct culprit for DSBs.