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Fanconi anaemia (FA) is an autosomal recessive disease characterized by bone marrow failure, variable congenital malformations and predisposition to malignancies1,2. Cells derived from FA patients show elevated levels of chromosomal breakage and an increased sensitivity to bifunctional alkylating agents such as mitomycin C (MMC) and diepoxybutane (DEB)3,4. Five complementation groups have been identified by somatic cell methods5,6, and we have cloned the gene defective in group C (FAC)7. To understand the in vivo role of this gene, we have disrupted murine Fac and generated mice homozygous for the targeted allele. The −/− mice did not exhibit developmental abnormalities nor haematologic defects up to 9 months of age. However, their spleen cells had dramatically increased numbers of chromosomal aberrations in response to MMC and DEB. Homozygous male and female mice also had compromised gametogenesis, leading to markedly impaired fertility, a characteristic of FA patients2. Thus, inactivation of Fac replicates some of the features of the human disease.

Bloom syndrome is a disorder associated with genomic instability that causes affected people to be prone to cancer. Bloom cell lines show increased sister chromatid exchange, yet are proficient in the repair of various DNA lesions. The underlying cause of this disease are mutations in a gene encoding a RECQ DNA helicase. Using embryonic stem cell technology, we have generated viable Bloom mice that are prone to a wide variety of cancers. Cell lines from these mice show elevations in the rates of mitotic recombination. We demonstrate that the increased rate of loss of heterozygosity (LOH) resulting from mitotic recombination in vivo constitutes the underlying mechanism causing tumour susceptibility in these mice.

BRCA1 activity may be regulated by the ubiquitin-modified form of the Fanconi anemia D2 protein. Other proteins involved in DNA repair and genomic stability that are also found in the same subnuclear compartments may be similarly regulated.