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KLF5 loss sensitizes cells to ATR inhibition and is synthetic lethal with ARID1A deficiency

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Listed:
  • Samah W. Awwad

    (University of Cambridge
    University of Cambridge)

  • Colm Doyle

    (University of Cambridge)

  • Josie Coulthard

    (University of Cambridge)

  • Aldo S. Bader

    (University of Cambridge
    University of Cambridge)

  • Nadia Gueorguieva

    (University of Cambridge
    University of Cambridge)

  • Simon Lam

    (University of Cambridge
    University of Cambridge)

  • Vipul Gupta

    (University of Cambridge)

  • Rimma Belotserkovskaya

    (University of Cambridge
    University of Cambridge)

  • Tuan-Anh Tran

    (University of Cambridge)

  • Shankar Balasubramanian

    (University of Cambridge
    University of Cambridge)

  • Stephen P. Jackson

    (University of Cambridge
    University of Cambridge
    University of Cambridge)

Abstract

ATR plays key roles in cellular responses to DNA damage and replication stress, a pervasive feature of cancer cells. ATR inhibitors (ATRi) are in clinical development for treating various cancers, including those with high replication stress, such as is elicited by ARID1A deficiency, but the cellular mechanisms that determine ATRi efficacy in such backgrounds are unclear. Here, we have conducted unbiased genome-scale CRISPR screens in ARID1A-deficient and proficient cells treated with ATRi. We found that loss of transcription factor KLF5 has severe negative impact on fitness of ARID1A-deficient cells while hypersensitising ARID1A-proficient cells to ATRi. KLF5 loss induced replication stress, DNA damage, increased DNA-RNA hybrid formation, and genomic instability upon ATR inhibition. Mechanistically, we show that KLF5 protects cells from replication stress, at least in part through regulating BRD4 recruitment to chromatin. Overall, our work identifies KLF5 as a potential target for eradicating ARID1A-deficient cancers.

Suggested Citation

  • Samah W. Awwad & Colm Doyle & Josie Coulthard & Aldo S. Bader & Nadia Gueorguieva & Simon Lam & Vipul Gupta & Rimma Belotserkovskaya & Tuan-Anh Tran & Shankar Balasubramanian & Stephen P. Jackson, 2025. "KLF5 loss sensitizes cells to ATR inhibition and is synthetic lethal with ARID1A deficiency," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55637-5
    DOI: 10.1038/s41467-024-55637-5
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    References listed on IDEAS

    as
    1. Fred C. Lam & Yi Wen Kong & Qiuying Huang & Tu-Lan Han & Amanda D. Maffa & Ekkehard M. Kasper & Michael B. Yaffe, 2020. "BRD4 prevents the accumulation of R-loops and protects against transcription–replication collision events and DNA damage," Nature Communications, Nature, vol. 11(1), pages 1-20, December.
    2. Chris T. Williamson & Rowan Miller & Helen N. Pemberton & Samuel E. Jones & James Campbell & Asha Konde & Nicholas Badham & Rumana Rafiq & Rachel Brough & Aditi Gulati & Colm J. Ryan & Jeff Francis & , 2016. "ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A," Nature Communications, Nature, vol. 7(1), pages 1-13, December.
    3. Morgane Macheret & Thanos D. Halazonetis, 2018. "Intragenic origins due to short G1 phases underlie oncogene-induced DNA replication stress," Nature, Nature, vol. 555(7694), pages 112-116, March.
    4. Stephen P. Jackson & Jiri Bartek, 2009. "The DNA-damage response in human biology and disease," Nature, Nature, vol. 461(7267), pages 1071-1078, October.
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