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RPA exhaustion activates SLFN11 to eliminate cells with heightened replication stress

Tyler H Stanage1, Shudong Li1, Sandra Segura-Bayona1

  • 1DSB Repair Laboratory, The Francis Crick Institute, London, UK.

Nature Cell Biology
|January 9, 2026
PubMed

Insights

The study reveals that replication protein A (RPA) exhaustion triggers SLFN11 activation and cancer cell death, particularly when DNA repair pathways like PrimPol are deficient. This finding offers new insights into cancer chemotherapy resistance.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • The protein SLFN11 (ச்சாங்-லி-ஃபங்-11) is epigenetically silenced in many cancers, contributing to chemoresistance.
  • SLFN11 activation leads to translation shutdown and apoptosis, but its DNA damage-induced activation mechanism is not fully understood.

Purpose of the Study:

  • To elucidate the mechanism by which DNA damage activates SLFN11, especially in cancer cells with impaired DNA repair.
  • To identify key factors and pathways involved in SLFN11 activation and its role in cisplatin sensitivity.

Main Methods:

  • CRISPR-based genetic screens were employed to identify determinants of cisplatin sensitivity.
  • Cellular assays were used to investigate the roles of replication protein A (RPA), primase-polymerase (PrimPol), and the USP1-WDR48 complex in SLFN11 activation.
  • Chemical inhibition of DNA polymerase α was used to induce replication stress.

Main Results:

  • SLFN11 is critical for cisplatin sensitivity in cells lacking PrimPol-mediated repriming.
  • Replication protein A (RPA) exhaustion and single-stranded DNA exposure activate SLFN11 and cell death in PrimPol-deficient cells.
  • The USP1-WDR48 deubiquitinase complex positively modulates SLFN11 activation in PrimPol-deficient cells, highlighting a reliance on the Fanconi anaemia pathway.
  • Chemical inhibition of DNA polymerase α leads to RPA exhaustion and SLFN11-dependent cell death.

Conclusions:

  • Replication protein A (RPA) exhaustion serves as a general mechanism for SLFN11 activation under conditions of heightened replication stress.
  • Understanding SLFN11 activation in DNA repair-deficient cells provides potential therapeutic strategies for overcoming chemoresistance in cancer.

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