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Updated: Jun 18, 2026

Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis
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Published on: June 27, 2020

FANCA-dependent FEN1 recruitment suppresses transcription-replication conflicts and PARPi sensitivity

Qinhong Wang1, Simon W Ellington2, Paolo Guerra3

  • 1Lineberger Comprehensive Cancer Center, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Radiation Oncology, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Molecular Cell
|June 16, 2026
PubMed

Insights

FANCA deficiency causes synthetic lethality with PARP1 inhibitors (PARPi) by disrupting DNA replication, not homologous recombination repair. This uncovers a new vulnerability for PARPi beyond HR-deficient cancers.

Area of Science:

  • Genetics
  • Molecular Biology
  • Cancer Research

Background:

  • Synthetic lethality (SL) with PARP1 inhibitors (PARPi) is established for homologous recombination (HR)-deficient cancers.
  • The broader applicability of PARPi beyond HR deficiency is not well understood.

Purpose of the Study:

  • To identify new genetic contexts conferring PARPi SL beyond HR deficiency.
  • To elucidate the molecular mechanisms underlying FANCA deficiency-mediated PARPi SL.

Main Methods:

  • In vivo CRISPR screening in diverse cancer models.
  • Analysis of DNA replication fork dynamics, Okazaki fragment maturation, and RPA recruitment.
  • Investigation of transcription-replication conflicts (TRCs) and their resolution.

Main Results:

  • FANCA deficiency was identified as a driver of tumor progression and PARPi SL.
  • FANCA loss disrupts FEN1 recruitment, leading to defective Okazaki fragment maturation and RPA exhaustion under PARPi.
  • FANCA loss sensitizes HR-proficient cells to PARPi by promoting lagging-strand TRCs, a phenotype modulated by RNA polymerase II activity and RNase H.

Conclusions:

  • FANCA deficiency represents a context-specific vulnerability to PARPi, extending its therapeutic potential.
  • FANCA is crucial for suppressing TRCs and maintaining genomic stability under oncogenic stress, particularly in lagging-strand DNA synthesis.
Keywords:
Okazaki fragment maturationPARP inhibitor sensitivityreplication stresssingle-stranded DNA gapssynthetic lethalitytranscription-replication conflicts

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