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

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 () and Haico Attikum ()
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Bert Kooij: Leiden University Medical Center
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
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
Haico Attikum: Leiden University Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51090-6

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