DNA interstrand crosslink repair requires several classes of proteins, including structure-specific endonucleases and Fanconi anemia proteins. SLX4, which coordinates three separate endonucleases, was recently recognized as an important regulator of DNA repair. Here we report the first human individuals found to have biallelic mutations in SLX4. These individuals, who were previously diagnosed as having Fanconi anemia, add SLX4 as an essential component to the FA-BRCA genome maintenance pathway.
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
de Winter, J.P. & Joenje, H. The genetic and molecular basis of Fanconi anemia. Mutat. Res. 668, 11–19 (2009).
Vaz, F. et al. Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nat. Genet. 42, 406–409 (2010).
Singh, T.R. et al. Impaired FANCD2 monoubiquitination and hypersensitivity to camptothecin uniquely characterize Fanconi anemia complementation group M. Blood 114, 174–180 (2009).
Shimamura, A. et al. A novel diagnostic screen for defects in the Fanconi anemia pathway. Blood 100, 4649–4654 (2002).
Fekairi, S. et al. Human SLX4 is a Holliday junction resolvase subunit that binds multiple DNA repair/recombination endonucleases. Cell 138, 78–89 (2009).
Svendsen, J.M. et al. Mammalian BTBD12/SLX4 assembles a Holliday junction resolvase and is required for DNA repair. Cell 138, 63–77 (2009).
Andersen, S.L. et al. Drosophila MUS312 and the vertebrate ortholog BTBD12 interact with DNA structures-specific endonucleases in DNA repair and recombination. Mol. Cell 35, 128–135 (2009).
Muñoz, I.M. et al. Coordination of structure-specific nucleases by human SLX4/BTBD12 is required for DNA repair. Mol. Cell 35, 116–127 (2009).
van Vuren, A.J. et al. Evidence for a repair enzyme complex involving ERCC1 and complementing activities of ERCC4, ERCC11 and xeroderma pigmentosum group F. EMBO J. 12, 3693–3701 (1993).
Crossan, G.P. et al. Disruption of mouse Slx4, a regulator of structure-specific nucleases, phenocopies Fanconi anemia. Nat. Genet. advance online publication, doi:10.1038/ng.752 (16 January 2011).
Jaspers, N.G.J. et al. First reported patient with human ERCC1 deficiency has cerebro-oculo-facio-skeletal syndrome with a mild defect in nucleotide excision repair and severe developmental failure. Am. J. Hum. Genet. 80, 457–466 (2007).
Ahmad, A. et al. Mislocalization of XPF-ERCC1 nuclease contributes to reduced DNA repair in XP-F patients. PLoS Genet. 6, e1000871 (2010).
Joenje, H. et al. Classification of Fanconi anemia patients by complementation analysis: evidence for a fifth genetic subtype. Blood 86, 2156–2160 (1995).
We thank the affected individuals and their families for contributing to this study. We also thank A. Raams, R. Friedl, B. Gottwald and S. Darchinger for expert technical assistance. We acknowledge I. Carr for Phaser software, R. Kanaar for RAD51 antiserum and K.J. Patel for mouse Slx4 cDNA. Financial support was from the Cancer Center Amsterdam-VU Medisch Centrum Institute for Cancer and Immunology (CCA/V-ICI) Amsterdam (to C.S.), the Dutch Cancer Society (to H.J.), Schroeder-Kurth-Fund (to D.S.) and the Medical Research Council UK (to J.R.).
The authors declare no competing financial interests.
About this article
Cite this article
Stoepker, C., Hain, K., Schuster, B. et al. SLX4, a coordinator of structure-specific endonucleases, is mutated in a new Fanconi anemia subtype. Nat Genet 43, 138–141 (2011). https://doi.org/10.1038/ng.751
Chromosome 16p13.3 Contiguous Gene Deletion Syndrome including the SLX4, DNASE1, TRAP1, and CREBBP Genes Presenting as a Relatively Mild Rubinstein–Taybi Syndrome Phenotype: A Case Report of a Saudi Boy
Case Reports in Genetics (2020)
Resolvases, Dissolvases, and Helicases in Homologous Recombination: Clearing the Road for Chromosome Segregation
Annual Review of Cancer Biology (2019)
Methods for Enhancing Clustered Regularly Interspaced Short Palindromic Repeats/Cas9-Mediated Homology-Directed Repair Efficiency
Frontiers in Genetics (2019)