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G-quadruplex homeostasis is a determinant of PARP inhibitor toxicity in BRCA2-deficient cells

Abhishek Bharadwaj Sharma1,2, Joanna Krwawicz1, Leandre Tappenden1

  • 1Department of Biochemistry, University of Oxford, South Parks Road, Oxford, UK.

Nature Communications
|July 3, 2026
PubMed

Insights

G-quadruplex DNA structures drive PARP inhibitor toxicity in BRCA2-deficient tumors. Suppressing these structures via the HAPSTR1/HUWE1 pathway confers resistance, offering new therapeutic strategies.

Area of Science:

  • Cancer Biology
  • DNA Repair Mechanisms
  • Genomic Instability

Background:

  • PARP inhibitors are crucial for treating homologous recombination (HR)-deficient tumors, like those with BRCA2 mutations.
  • PARP inhibition induces replication stress, necessitating HR for DNA repair.
  • The specific DNA lesions driving PARP inhibitor toxicity and BRCA2 dependence remain unclear.

Purpose of the Study:

  • To investigate the role of G-quadruplex (G4) DNA structures in PARP inhibitor response.
  • To identify mechanisms that suppress G4 levels and influence PARP inhibitor sensitivity.

Main Methods:

  • Cellular assays to assess G4 DNA levels, replication stress, and DNA damage.
  • Investigated the roles of HAPSTR1, BRCA2, HUWE1, and PARP1/PARP2 in G4 suppression.
  • Utilized proteasome degradation assays to study HAPSTR1 turnover.

Main Results:

  • Elevated G4 DNA levels correlate with PARP inhibitor toxicity and genome instability.
  • HAPSTR1 and BRCA2 act in parallel pathways to suppress G4 structures during S-phase.
  • Disruption of HAPSTR1 or BRCA2 leads to G4-replication conflicts and DNA damage.
  • HUWE1-mediated degradation of HAPSTR1 suppresses G4 levels, conferring PARP inhibitor resistance in BRCA2-deficient cells.

Conclusions:

  • G4 DNA structures are key determinants of PARP inhibitor toxicity.
  • The HAPSTR1/HUWE1 axis is essential for suppressing G4 structures and conferring PARP inhibitor resistance.
  • Targeting G4 structures or the HAPSTR1/HUWE1 pathway may overcome PARP inhibitor resistance.

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