Tumour suppressors: A guardian and a suppressor

Abstract

expect to be conserved across all species. And yet some of them use a surprising variety of molecular mechanisms. A recent report by McPherson et al. shows that the MUS81 endonuclease, which is involved in processing branched DNA structures in yeast, such as those found in stalled replication forks, is required in mammals for genomic stability and tumour suppression. To clarify the role of Mus81 in vivo, the authors knocked out the gene in mice. Based on the role of Mus81 in yeast, they expected the mice to show meiotic recombination defects, such as infertility. To their surprise, the animals were fertile with no defects in gametogenesis. Normal gene targeting in the Mus81 embryonic-stem-cell lineage, and Band T-cell lineages (the ontogeny of which requires DNA rearrangements), confirmed that Mus81 is not required for a cell to cope with double-stranded DNA breaks. But Mus81 knockout mice do have a phenotype — mutant embryonic stem cells are hypersensitive to the alkylating agent mitomycin C, indicating that the gene might be involved in repairing mitomycin-C-induced DNA interstrand crosslinks. Mus81 also seems to act as a haploinsufficient genome caretaker — loss of even one copy of Mus81 leads to aneuploidy and other chromosomal defects. Although, at first glance, mutant mice seem to be normal, the authors found that only 27% of homozygotes and 50% of heterozygotes were healthy and survived through their first year. Many had tumours, mainly non-Hodgkin’s lymphomas, that at the cellular level were associated with aneuploidy. Because Mus81 homozygotes and heterozygotes were equally susceptible to cancer, both copies of Mus81 must be required for its tumoursuppressor function — just as two copies are required for genome integrity. Although MUS81 is not alone in being a haploinsufficient tumour suppressor, it is at odds with the common view that tumorigenesis requires the loss of both copies of a tumour suppressor. Mechanistically speaking, the genomic instability caused by Mus81 haploinsufficiency might facilitate tumorigenesis, for example, in preneoplastic lymphocytes. However, it remains to be seen whether the model that the authors propose is correct — that is, that a 50% reduction in the amount of MUS81 protein in heterozygotes is not sufficient to resolve intermediate DNA structures that form during DNA repair. Magdalena Skipper Editor, Nature Reviews Genetics

DOI: 10.1038/nrc1426

Cite this paper

@article{Skipper2004TumourSA, title={Tumour suppressors: A guardian and a suppressor}, author={Magdalena Skipper}, journal={Nature Reviews Cancer}, year={2004}, volume={4}, pages={578-578} }