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Replication protein A protects lagging strand gaps, restricting PARP inhibitor-induced synthetic lethality in

Pamela S VanderVere-Carozza1, Matthew R Jordan1,2, Joy E Garrett3

  • 1Department of Biochemistry, Molecular Biology and Pharmacology, Indiana University School of Medicine, Indianapolis, IN 46202, United States.

Nucleic Acids Research
|April 28, 2026
PubMed

Insights

This study reveals how inhibiting Replication Protein A (RPA) causes exhaustion, leading to genome instability and cell death in BRCA1-deficient cancers. Targeting RPA offers a new therapeutic strategy for these cancers.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • Replication Protein A (RPA) is crucial for maintaining genome integrity during DNA replication, repair, and recombination.
  • RPA binds single-stranded DNA (ssDNA) and plays a vital role in protecting it from degradation and aberrant structures.

Purpose of the Study:

  • To elucidate the mechanisms by which a small-molecule RPA inhibitor induces functional RPA exhaustion.
  • To investigate the therapeutic potential of targeting RPA in cancer models, particularly BRCA1-deficient cancers.

Main Methods:

  • Utilized non-small cell lung cancer and BRCA1-deficient breast and ovarian cancer models.
  • Employed small-molecule RPA inhibitors and PARP inhibitors.
  • Combined genetic and pharmacologic approaches to induce ssDNA accumulation and RPA exhaustion in vivo.

Main Results:

  • RPA is critical for sustaining replication fork speed and facilitating restart after stalling.
  • RPA inhibition exacerbates genome instability in BRCA1-deficient cancers treated with PARP inhibitors, causing chromosome shattering and cell death.
  • Targeting RPA exhaustion in BRCA1-deficient breast cancer models demonstrated therapeutic efficacy.

Conclusions:

  • RPA exhaustion is a viable therapeutic strategy for cancers with replication stress, especially BRCA1-deficient cancers.
  • Understanding RPA's role in ssDNA protection provides a mechanistic framework for developing novel cancer therapies.

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