Disruption of mouse Slx4, a regulator of structure-specific nucleases, phenocopies Fanconi anemia

Crossan, G. P. et al. (2011) Disruption of mouse Slx4, a regulator of structure-specific nucleases, phenocopies Fanconi anemia. Nature Genetics, 43(2), pp. 147-152. (doi: 10.1038/ng.752) (PMID:21240276) (PMCID:PMC3624090)

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The evolutionarily conserved SLX4 protein, a key regulator of nucleases, is critical for DNA damage response. SLX4 nuclease complexes mediate repair during replication and can also resolve Holliday junctions formed during homologous recombination. Here we describe the phenotype of the Btbd12 knockout mouse, the mouse ortholog of SLX4, which recapitulates many key features of the human genetic illness Fanconi anemia. Btbd12-deficient animals are born at sub-Mendelian ratios, have greatly reduced fertility, are developmentally compromised and are prone to blood cytopenias. Btbd12−/− cells prematurely senesce, spontaneously accumulate damaged chromosomes and are particularly sensitive to DNA crosslinking agents. Genetic complementation reveals a crucial requirement for Btbd12 (also known as Slx4) to interact with the structure-specific endonuclease Xpf-Ercc1 to promote crosslink repair. The Btbd12 knockout mouse therefore establishes a disease model for Fanconi anemia and genetically links a regulator of nuclease incision complexes to the Fanconi anemia DNA crosslink repair pathway.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Lewis, Dr David
Authors: Crossan, G. P., van der Weyden, L., Rosado, I. V., Langevin, F., Gaillard, P.-H. L., McIntyre, R. E., Gallagher, F., Kettunen, M. I., Lewis, D. Y., Brindle, K., Arends, M. J., Adams, D. J., and Patel, K. J.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Nature Genetics
Publisher:Nature Research
ISSN (Online):1546-1718

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