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Genomic instability

Expanding the reach of Fanconi anaemia

Nature Reviews Cancer volume 11, pages 158–159 (2011)Cite this article

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The FA pathway is thought to mediate the repair of DNA interstrand crosslinks (ICLs) at replication forks. Therefore, cells from patients with FA are hypersensitive to DNA crosslinking agents, such as mitomycin C (MMC) and cisplatinum, and they exhibit high levels of chromosome instability, particularly radial chromosome fusions. Depletion of SLX4 from human cells has been shown to cause sensitivity to crosslinking agents; so, Crossan and colleagues generated Slx4−/− mice to investigate. The mice had growth retardation, developmental defects and reduced survival. They also found reduced white blood cell and platelet counts, and erythrocytes from these mice exhibited a 2.5-fold increase in micronuclei, which is indicative of genomic instability. Metaphase spreads of Slx4−/− mouse embryonic fibroblasts (MEFs) showed increased chromatid breaks and complex radial chromosome fusions, which increased with MMC treatment. Moreover, the Slx4−/− MEFs were hypersensitive to MMC and cisplatinum. These phenotypes are consistent with those of patients with FA, and cells derived from them, suggesting that SLX4 might be a member of the FA pathway.

SLX4 mutation ... defines a new FA complementation group: FA-P

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ORIGINAL RESEARCH PAPERS

  1. Crossan, G. P. et al. Disruption of mouse Slx4, a regulator of structure-specific nucleases, phenocopies Fanconi anemia. Nature Genet. 16 Jan 2011 (doi: 10.1038/ng.752)

  2. Kim, Y. et al. Mutations of the SLX4 gene in Fanconi anemia. Nature Genet. 16 Jan 2011 (doi: 10.1038/ng.750)

  3. Stoepker, C. et al. SLX4, a coordinator of structure-specific endonucleases, is mutated in a new Fanconi anemia subtype. Nature Genet. 16 Jan 2011 (doi: 10.1038/ng.751)

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Authors
  1. Gemma K. Alderton
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Alderton, G. Expanding the reach of Fanconi anaemia. Nat Rev Cancer 11, 158–159 (2011). https://doi.org/10.1038/nrc3027

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