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

  • Mol Cell. 2026 Jun 16:S1097-2765(26)00351-5. doi: 10.1016/j.molcel.2026.05.027.
Qinhong Wang  1 ,  Simon W Ellington  2 ,  Paolo Guerra  3 ,  Faeze Gharibpoor  2 ,  Dennis A Simpson  2 ,  Min-Guk Cho  2 ,  Adriana Beltran  4 ,  Gaorav P Gupta  5
Affiliations
  • 1. Lineberger 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.
  • 2. Lineberger Comprehensive Cancer Center, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 3. Lineberger Comprehensive Cancer Center, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Curriculum in Genetics and Molecular Biology, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 4. Department of Genetics, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 5. Lineberger 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; Curriculum in Genetics and Molecular Biology, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: [email protected].
PMID: 42302790 DOI: 10.1016/j.molcel.2026.05.027
Abstract

Synthetic lethality (SL) underlies the success of PARP1 inhibitors (PARPi) in treating homologous recombination (HR)-deficient cancers, yet their broader applicability beyond HR deficiency remains poorly defined. Here, we performed an in vivo CRISPR screen that identifies FANCA deficiency as a driver of tumor progression and PARPi SL, validated across diverse human Cancer models. Notably, FANCA loss does not impair HR but instead disrupts FEN1 recruitment to replication forks, leading to defective Okazaki fragment maturation, lagging-strand single-strand DNA gap accumulation, and RPA exhaustion upon PARPi treatment. Additionally, FANCA loss in oncogene-expressing cells promotes transcription-replication conflict (TRC) accumulation selectively on the lagging strand and sensitizes HR-proficient cells to PARPi, a phenotype reversible by RNA polymerase II inhibition or RNase H overexpression. Together, these findings identify FANCA deficiency as a context-specific PARPi vulnerability and establish FANCA as a key suppressor of TRCs required for genomic stability under oncogenic replication stress.

Keywords
Okazaki fragment maturation; PARP inhibitor sensitivity; replication stress; single-stranded DNA gaps; synthetic lethality; transcription-replication conflicts.
Products