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ATR-dependent phosphorylation of the histone acetyltransferase HBO1 suppresses chromatin binding and promotes

Chunyan Zong1, Jiamin Zhang2, Zhe Zhang3

  • 1Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China; Institute of Translational Medicine, National Facility for Translational Medicine, Shanghai Jiao Tong University, Shanghai, China; Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

The Journal of Biological Chemistry
|August 10, 2026
PubMed

Insights

Histone acetyltransferase binding to ORC1 (HBO1) is an oncoprotein targeted by WM-3835. ATR is a novel HBO1 partner, acting as a biomarker for predicting sensitivity to HBO1 inhibition and reducing toxicity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Histone acetyltransferase binding to ORC1 (HBO1) is implicated as an oncoprotein.
  • HBO1 inhibition via WM-3835 shows therapeutic potential but faces toxicity concerns due to ubiquitous expression.
  • Biomarkers are needed to predict patient response and minimize side effects of HBO1 inhibitors.

Purpose of the Study:

  • To identify novel interacting partners of HBO1.
  • To elucidate the role of HBO1 in DNA replication stress response.
  • To discover biomarkers for predicting sensitivity to the HBO1 inhibitor WM-3835.

Main Methods:

  • Co-immunoprecipitation to identify HBO1 interacting partners.
  • Western blotting and gene expression analysis to study HBO1's role in DNA replication stress.
  • Functional assays involving mutated HBO1 and ATR inhibition to assess WM-3835 sensitivity.

Main Results:

  • ATR was identified as a novel interacting partner of HBO1.
  • HBO1 regulates DNA replication stress in an ATR-dependent manner via phosphorylation at Ser50/53.
  • ATR inhibition reduced sensitivity to WM-3835, and mutated HBO1 (S50/53A) mimicked WM-3835 effects.

Conclusions:

  • HBO1 plays a critical role in regulating replication stress through ATR.
  • ATR is a potential predictive biomarker for WM-3835 therapy.
  • Targeting the HBO1-ATR axis may offer a more precise approach to cancer treatment.
Keywords:
ATRHBO1histone acetyltransferasephosphorylationreplication stress

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