2. Academic Validation
  3. Chromatin Perturbation Promotes Susceptibility to Hypomethylating Agents

Chromatin Perturbation Promotes Susceptibility to Hypomethylating Agents

  • bioRxiv. 2025 Jul 31:2025.07.28.666975. doi: 10.1101/2025.07.28.666975.
Constanze Schneider 1 2,  Gabriela Alexe 1 2,  Lucy A Merickel 1,  Ashleigh Meyer 1,  Michelle L Swift 3,  Rodolfo B Serafim 1,  Allen T Basanthakumar 1,  Audrey Taillon 1,  Silvi Salhotra 1,  Fabio Boniolo 1 2,  Sander Lambo 1 2,  Yara Rodriguez 1 2,  Björn Häupl 4 5 6,  Rani E George 1,  David E Root 2,  Thomas Oellerich 4 5 6,  Volker Hovestadt 1 2,  Dipanjan Chowdhury 3 7,  Kimberly Stegmaier 1 2
Affiliations

Affiliations

  • 1 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
  • 2 The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 3 Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 4 Goethe University Frankfurt, University Hospital, Frankfurt am Main, Germany.
  • 5 Frankfurt Cancer Institute, Goethe University, Frankfurt am Main, Germany.
  • 6 German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Frankfurt am Main, Germany.
  • 7 Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
PMID: 40766615 DOI: 10.1101/2025.07.28.666975
Abstract

Cancer-directed drugs are often clinically deployed without definitive understanding of their molecular mechanisms of action (MOA). Hypomethylating agents (HMAs), which result in the degradation of the DNA Methyltransferase 1 (DNMT1), have been deployed for decades in the treatment of haematological malignancies1,2. The precise mechanism of action of these drugs, however, has been debated, rendering the design of rational combination therapies challenging. Here, we identified the deubiquitinating enzyme USP48 as a crucial regulator of posttranslational histone modification in the context of DNA demethylation. USP48 loss selectively enhances response to DNMT1 inhibition, leading to a rapid induction of cell death. We demonstrate that USP48 is localized at sites of DNA damage and deubiquitinates H2A variants and proteins important for DNA damage repair. Functionally, loss of USP48 triggers an increase in chromatin accessibility upon HMA treatment, rendering AML cells more susceptible to DNA damage. Our results support USP48 as a posttranslational histone modifier for chromatin stability and DNA damage in response to HMA-related DNA demethylation. These findings propose USP48 as a new target for combination therapy with HMAs for acute myeloid leukaemia (AML).

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