The Fanconi anemia core complex promotes CtIP-dependent end resection to drive homologous recombination at DNA double-strand breaks
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.
Authors
- Brian A. Joughin (ORCID: https://orcid.org/0000-0003-1022-9450)
- Pau Creixell
- Marcel A.T.M. van Vugt (ORCID: https://orcid.org/0000-0002-3202-4678)
- Merula Stout (ORCID: https://orcid.org/0000-0001-6643-7860)
- Bert van de Kooij (ORCID: https://orcid.org/0000-0003-1042-8409)
- Fenna J. van der Wal (ORCID: https://orcid.org/0000-0002-8536-7359)
- Julia Vornberger (ORCID: https://orcid.org/0000-0002-3139-8168)
- Magdalena B. Rother
- Wouter W. Wiegant (ORCID: https://orcid.org/0000-0003-3137-6433)
- Michael B. Yaffe (ORCID: https://orcid.org/0000-0002-9547-3251)
- Matthias Altmeyer (ORCID: https://orcid.org/0000-0003-3780-1170)
- Haico van Attikum (ORCID: https://orcid.org/0000-0001-8590-0240)
Institutions
- Beth Israel Deaconess Medical Center (US)
- University Medical Center Groningen (NL)
- Harvard University (US)
- University of Groningen (NL)
- University of Zurich (CH)
- University of Cambridge (GB)
- Leiden University Medical Center (NL)
- Center for Cancer Research (US)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-16
- DOI
- https://doi.org/10.1038/s41467-024-51090-6
- Citations
- 26
- Primary Topic
- DNA Repair Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 5.85
Funders
- National Science Foundation
- Institute for Research in Biomedicine
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
- Cancer Research UK
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Universiteit Leiden
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Leids Universitair Medisch Centrum
- Universitair Medisch Centrum Groningen
- National Cancer Institute