The Fanconi anemia core complex promotes CtIP-dependent end resection to drive homologous recombination at DNA double-strand breaks.
Humans
DNA Breaks, Double-Stranded
Fanconi Anemia Complementation Group D2 Protein
/ metabolism
Fanconi Anemia Complementation Group L Protein
/ metabolism
Ubiquitin-Conjugating Enzymes
/ metabolism
Homologous Recombination
Nuclear Proteins
/ metabolism
Carrier Proteins
/ metabolism
CRISPR-Cas Systems
Ubiquitination
Fanconi Anemia
/ genetics
Endodeoxyribonucleases
/ metabolism
HEK293 Cells
Recombinational DNA Repair
DNA Repair
DNA End-Joining Repair
DNA Helicases
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
16 Aug 2024
16 Aug 2024
Historique:
received:
11
09
2023
accepted:
17
07
2024
medline:
17
8
2024
pubmed:
17
8
2024
entrez:
16
8
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39152113
doi: 10.1038/s41467-024-51090-6
pii: 10.1038/s41467-024-51090-6
doi:
Substances chimiques
Fanconi Anemia Complementation Group D2 Protein
0
RBBP8 protein, human
EC 3.1.-
Fanconi Anemia Complementation Group L Protein
EC 2.3.2.27
FANCD2 protein, human
0
FANCL protein, human
EC 2.3.2.27
Ubiquitin-Conjugating Enzymes
EC 2.3.2.23
UBE2T protein, human
EC 2.3.2.23
Nuclear Proteins
0
Carrier Proteins
0
FANCM protein, human
EC 3.6.1.-
Endodeoxyribonucleases
EC 3.1.-
DNA Helicases
EC 3.6.4.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
7076Subventions
Organisme : EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)
ID : ERC-CoG-617485
Organisme : Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organisation for Scientific Research)
ID : VI.C.182.052
Organisme : KWF Kankerbestrijding (Dutch Cancer Society)
ID : BUIT 2015-7546
Organisme : Cancer Research UK (CRUK)
ID : C9545/A29580
Organisme : Cancer Research UK (CRUK)
ID : C9685/A26398
Organisme : Cancer Research UK (CRUK)
ID : C42454/A28596
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)
ID : 310030_197003
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : P30-CA14051
Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)
ID : R01-ES015339
Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)
ID : R35-ES028374
Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)
ID : R01-CA226898
Informations de copyright
© 2024. The Author(s).
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