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The Fanconi anemia core complex promotes CtIP-dependent end resection to drive homologous recombination at DNA double-strand breaks

Author

Listed:
  • Bert Kooij

    (Leiden University Medical Center
    Massachusetts Institute of Technology
    University of Groningen)

  • Fenna J. Wal

    (Leiden University Medical Center)

  • Magdalena B. Rother

    (Leiden University Medical Center)

  • Wouter W. Wiegant

    (Leiden University Medical Center)

  • Pau Creixell

    (Massachusetts Institute of Technology
    University of Cambridge)

  • Merula Stout

    (University of Zurich (UZH))

  • Brian A. Joughin

    (Massachusetts Institute of Technology)

  • Julia Vornberger

    (University of Zurich (UZH))

  • Matthias Altmeyer

    (University of Zurich (UZH))

  • Marcel A. T. M. Vugt

    (University of Groningen)

  • Michael B. Yaffe

    (Massachusetts Institute of Technology
    Harvard Medical School)

  • Haico Attikum

    (Leiden University Medical Center)

Abstract

During the repair of interstrand crosslinks (ICLs) a DNA double-strand break (DSB) is generated. The Fanconi anemia (FA) core complex, which is recruited to ICLs, promotes high-fidelity repair of this DSB by homologous recombination (HR). However, whether the FA core complex also promotes HR at ICL-independent DSBs, for example induced by ionizing irradiation or nucleases, remains controversial. Here, we identified the FA core complex members FANCL and Ube2T as HR-promoting factors in a CRISPR/Cas9-based screen. Using isogenic cell line models, we further demonstrated an HR-promoting function of FANCL and Ube2T, and of their ubiquitination substrate FANCD2. We show that FANCL and Ube2T localize at DSBs in a FANCM-dependent manner, and are required for the DSB accumulation of FANCD2. Mechanistically, we demonstrate that FANCL ubiquitin ligase activity is required for the accumulation of CtIP at DSBs, thereby promoting end resection and Rad51 loading. Together, these data demonstrate a dual genome maintenance function of the FA core complex and FANCD2 in promoting repair of both ICLs and DSBs.

Suggested Citation

  • Bert Kooij & Fenna J. Wal & Magdalena B. Rother & Wouter W. Wiegant & Pau Creixell & Merula Stout & Brian A. Joughin & Julia Vornberger & Matthias Altmeyer & Marcel A. T. M. Vugt & Michael B. Yaffe & , 2024. "The Fanconi anemia core complex promotes CtIP-dependent end resection to drive homologous recombination at DNA double-strand breaks," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51090-6
    DOI: 10.1038/s41467-024-51090-6
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    References listed on IDEAS

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