2. Academic Validation
  3. DAXX promotes SUMOylation of chromatin-trapped DNMT1

DAXX promotes SUMOylation of chromatin-trapped DNMT1

  • J Biochem. 2026 May 11;179(5):363-373. doi: 10.1093/jb/mvag011.
Shota Tanimoto 1,  Teh-Wei Wang 1 2,  Tomohiro Yabushita 3,  Yoshie Chiba 1,  Chieko Konishi 1,  Akinori Endo 4,  Yasushi Saeki 4 5,  Susumu Goyama 6,  Makoto Nakanishi 1,  Atsuya Nishiyama 1
Affiliations

Affiliations

  • 1 Division of Cancer Cell Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
  • 2 Project Division of Generative AI Utilization Aging Cells, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
  • 3 Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
  • 4 Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, 2-1-6 kamikitazawa, setagaya-ku, Tokyo 156-8506, Japan.
  • 5 Division of Protein Metabolism, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
  • 6 Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
PMID: 41679964 DOI: 10.1093/jb/mvag011
Abstract

The cytosine analogue 5-aza-2'-deoxycytidine (decitabine; DAC) covalently inhibits DNA Methyltransferase 1 (DNMT1), the maintenance DNA Methyltransferase, and induces SUMOylation of DNA-trapped DNMT1, promoting proteasomal degradation. However, the regulation of DNMT1 SUMOylation and its biological impact remain unclear. Here, using interphase Xenopus egg extracts that reconstitute maintenance DNA methylation in vitro, we identify death domain-associated protein (DAXX) as a regulator of SUMOylation on chromatin-retained, inactive DNMT1. First, adding 5-aza-dCTP, the triphosphate form of decitabine, induced DNMT1 accumulation on chromatin and robust SUMO2/3 conjugation. Chromatin mass spectrometry (CHROMASS) revealed DAXX enrichment on 5-aza-dCTP-treated chromatin in a SUMO-dependent manner, and DAXX depletion suppressed 5-aza-dCTP-induced DNMT1 SUMOylation. Furthermore, GSK-3484862, a non-covalent DNMT1 Inhibitor, drove DNMT1 accumulation on chromatin and triggered DAXX-dependent DNMT1 SUMOylation. We also demonstrated that DAXX loss increased decitabine sensitivity in the myeloid leukaemia (AML) cell line THP-1. Together, these findings show that DAXX promotes SUMOylation of DNMT1 trapped on DNA under both covalent and non-covalent trapping conditions.

Keywords

Xenopus egg extracts; DAXX; DNA methylation; DNMT1; SUMO.

Figures
Products