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<p>Histone modifications, including <i>N</i><sup>ε</sup>-lysine acetylation and methylation, play critical roles in the regulation of eukaryotic transcription. The addition of acetyl and methyl groups and removal of acetyl groups to histones involve redox-neutral reactions. Demethylation is O<sub>2</sub>-dependent, as reported for reactions catalysed by the 2-oxoglutarate-dependent hypoxia-inducible factor (HIF) hydroxylases, one of which is structurally related to the Jumonji-C (JmjC) histone demethylases. We screened for substrates of the HIF-regulated JmjC lysine demethylase KDM3A and unexpectedly observed that purified recombinant KDM3A catalyses oxidation of the <i>N</i><sup>ε</sup>-acetyl group of the Lys-9 of histone H3 (H3K9ac) giving an <i>N</i><sup>ε</sup>-hydroxyacetylated product (H3K9acOH). Here we show that <i>N</i><sup>ε</sup>-hydroxyacetyl-lysine is recognized by proteins known to bind to H3K9ac, including histone deacetylases and the YEATS domain-containing AF9. Studies employing an <i>N</i><sup>ε</sup>-hydroxyacetyl-lysine selective antibody and mass spectrometry support the cellular relevance of <i>N</i><sup>ε</sup>-hydroxyacetyl-lysine. Our combined biochemical and cellular results provide evidence for an unanticipated O<sub>2</sub>-mediated link between histone lysine <i>N</i><sup>ε</sup>-acetylation and JmjC catalysis.</p><p></p>

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KDM3A catalyses the oxidation of acetyl-lysine to hydroxyacetyl-lysine on histone H3K9

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月15日

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  • Roman Belle,
  • John-Paul Bukowski,
  • Rachel Schiller,
  • Ronald Cutler,
  • Eidarus Salah,
  • Robert S. Dawber,
  • Anthony Tumber,
  • Joanna Bonnici,
  • Jessica D. Kindrick,
  • Loane Serrano,
  • Patrick Rabe,
  • Catrine Johansson,
  • Marie-Hélène Ruchaud,
  • Richard J. Hopkinson,
  • William D. Figg, Sr,
  • Paul E. Brennan,
  • David R. Mole,
  • Simone Sidoli,
  • Akane Kawamura,
  • Christopher J. Schofield

摘要

Histone modifications, including Nε-lysine acetylation and methylation, play critical roles in the regulation of eukaryotic transcription. The addition of acetyl and methyl groups and removal of acetyl groups to histones involve redox-neutral reactions. Demethylation is O2-dependent, as reported for reactions catalysed by the 2-oxoglutarate-dependent hypoxia-inducible factor (HIF) hydroxylases, one of which is structurally related to the Jumonji-C (JmjC) histone demethylases. We screened for substrates of the HIF-regulated JmjC lysine demethylase KDM3A and unexpectedly observed that purified recombinant KDM3A catalyses oxidation of the Nε-acetyl group of the Lys-9 of histone H3 (H3K9ac) giving an Nε-hydroxyacetylated product (H3K9acOH). Here we show that Nε-hydroxyacetyl-lysine is recognized by proteins known to bind to H3K9ac, including histone deacetylases and the YEATS domain-containing AF9. Studies employing an Nε-hydroxyacetyl-lysine selective antibody and mass spectrometry support the cellular relevance of Nε-hydroxyacetyl-lysine. Our combined biochemical and cellular results provide evidence for an unanticipated O2-mediated link between histone lysine Nε-acetylation and JmjC catalysis.