FANCJ DNA helicase is recruited to the replisome by AND-1 to ensure genome stability
Open accessPreprint — published as 10.1038/s44319-023-00044-y
Abstract
FANCJ is a DNA helicase linked to Fanconi anemia and frequently mutated in breast and ovarian cancers. If and how FANCJ is recruited to the replisome is unknown. Here, we report that FANCJ directly binds to AND-1 (the vertebrate ortholog of budding yeast Ctf4), a homo-trimeric protein adaptor that connects the CDC45/MCM2-7/GINS replicative DNA helicase with DNA polymerase α and several factors at DNA replication forks. We find that the interaction between FANCJ and AND-1 requires the integrity of an evolutionarily conserved Ctf4-interacting protein (CIP) box located between the FANCJ helicase motifs IV and V. Disruption of the FANCJ CIP box significantly reduces FANCJ association with the replisome, causing enhanced DNA damage, decreased replication fork recovery and fork asymmetry in stressful conditions. Cancer-relevant FANCJ CIP box variants display reduced AND-1-binding, a finding that suggests a potential role of the mutated FANCJ alleles in cancer predisposition.
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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Multistep mechanism of G-quadruplex resolution during DNA replication
Sato, K., Martin-Pintado, N., Post, H., Altelaar, M., & Knipscheer, P. (2021) · Science Advances · doi:10.1126/sciadv.abf8653 · Cited by 80 · cited 1× · see citing works
“…carried out in different systems (worms (Cheung et al, 2002), chicken DT40 (Sarkies et al, 2012) and human cells (Bharti et al, 2013) and Xenopus laevis cell-free egg extracts (Castillo Bosch et al, 2014; Sato et al, 2021)) pointed towards a prominent role of FANCJ in G4 DNA cellular metabolism.”
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- Authors
- Boavida, A., Napolitano, L. M. R., Santos, D., Cortone, G., Onesti, S., Jegadesan, N. K., Branzei, D., & Pisani, F. M.
- Affiliations
- University of Campania "Luigi Vanvitelli" (IT)
- Elettra-Sincrotrone Trieste S.C.p.A. (IT)
- National Research Council (IT)
- IFOM (IT)
- Corresponding author
- Pisani, Francesca M.
- ORCID
- Venue
- EMBO Reports
- Publisher
- openRxiv
- Published
- 2022-10-21
- Volume
- 25
- Issue
- 2
- Pages
- 876-901
- ISSN
- 1469-221X (ISSN-L)
- PMC
- PMC10897178
- OpenAlex
- W4390496416
- Cited by
- 11
- References
- 2
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 1
- FWCI
- 1.50
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- EMBO Reports (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Universitätsbibliographie, Universität Duisburg-Essen (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Fondazione AIRC per la ricerca sul cancro ETS (AIRC IG 20778, AIRC IG n. 25965, AIRC IG 23710, AIRC IG 18976)
- Queen Mary University of London
- European Commission (722729, 859853, HORIZON2020)
- Associazione Italiana per la Ricerca sul Cancro (IG 18976, IG 20778, 23710, IG 23710, 18976, AIRC IG n. 25965)
- McDonnell Center for Systems Neuroscience
- European Regional Development Fund
- Institute of Genetics
- H2020 Marie Skłodowska-Curie Actions (859853, 722729, HORIZON2020)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- FANCJ, Ctf4, replisome, replication stress, G-quadruplex, replication fork recovery, genome stability, Fanconi anemia, cancer susceptibility, DNA damage
- MeSH terms
- DNA, DNA Replication, Humans, Neoplasms, Genomic Instability, Minichromosome Maintenance Proteins
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