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Updated: May 12, 2025

Profiling Ubiquitin and Ubiquitin-like Dependent Post-translational Modifications and Identification of Significant Alterations
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MS CETSA deep functional proteomics uncovers DNA repair programs leading to gemcitabine resistance

Ying Yu Liang1, Khalidah Khalid1, Hai Van Le1

  • 1Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, 138673, Singapore.

Nature Communications
|May 7, 2025
PubMed

Insights

Gemcitabine resistance in lymphoma involves distinct cellular responses. Targeting ATR re-sensitizes resistant cells, revealing a key signaling node in DNA damage repair.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Cancer drug resistance involves complex cellular biochemistry.
  • Understanding resistance mechanisms at a systems level is challenging.
  • Gemcitabine is a key chemotherapy agent for diffuse large B cell lymphoma.

Purpose of the Study:

  • To investigate the biochemical responses to gemcitabine in resistant and sensitive lymphoma cells.
  • To identify key molecular pathways involved in gemcitabine resistance.
  • To explore potential therapeutic targets for overcoming gemcitabine resistance.

Main Methods:

  • Deep functional proteomics using Cellular Thermal Shift Assay (CETSA).
  • Analysis of biochemical changes in gemcitabine-resistant and sensitive diffuse large B cell lymphoma cell lines.
  • Assessment of drug effects on cellular pathways, apoptosis, and DNA damage responses.

Main Results:

  • Both sensitive and resistant cells initially show gemcitabine's effects on ribonucleotide reductase and DNA damage.
  • Resistant cells exhibit distinct DNA-damage signaling, cell cycle checkpoint activation, and translesion DNA synthesis.
  • An 'Auxiliary DNA Damage Repair' protein ensemble is induced in resistant cells.
  • ATR inhibition re-sensitizes resistant cells to gemcitabine.

Conclusions:

  • Gemcitabine resistance is characterized by specific biochemical adaptations in DNA damage and repair pathways.
  • ATR signaling is a critical node in mediating resistance to gemcitabine.
  • Targeting ATR offers a potential strategy to restore sensitivity to gemcitabine in resistant cancers.

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