SMC6 is an essential gene in mice, but a hypomorphic mutant in the ATPase domain has a mild phenotype with a range of subtle abnormalities

Smc5-6 is a highly conserved protein complex related to cohesin and condensin involved in the structural maintenance of chromosomes. In yeasts the Smc5-6 complex is essential for proliferation and is involved in DNA repair and homologous recombination. siRNA depletion of genes involved in the Smc5-6 complex in cultured mammalian cells results in sensitivity to some DNA damaging agents. In order to gain further insight into its role in mammals we have generated mice mutated in the Smc6 gene. A complete knockout resulted in early embryonic lethality, demonstrating that this gene is essential in mammals. However, mutation of the highly conserved serine-994 to alanine in the ATP hydrolysis motif in the SMC6 C-terminal domain, resulted in mice with a surprisingly mild phenotype. With the neo gene selection marker in the intron following the mutation, resulting in reduced expression of the SMC6 gene, the mice were reduced in size, but fertile and had normal lifespans. When the neo gene was removed, the mice had normal size, but detailed phenotypic analysis revealed minor abnormalities in glucose tolerance, haematopoiesis, nociception and global gene expression patterns. Embryonic fibroblasts derived from the ser994 mutant mice were not sensitive to killing by a range of DNA damaging agents, but they were sensitive to the induction of sister chromatid exchanges induced by ultraviolet light or mitomycin C. They also accumulated more oxidative damage than wild-type cells.

► Mice deleted for the SMC6 gene are inviable
► Mice mutated at Ser-994 in the ATPase domain of the Smc6 protein have a mild phenotype
► With the neo gene selection marker left in the intron following the mutation, resulting in reduced transcription of the SMC6 gene, the mice are proportionately small but they are fertile and have a normal lifespan
► Without the neo gene, the mice have a mild phenotype with normal size, but with minor changes in glucose tolerance, haematopoiesis and nociception.
► Mefs from the mutant mice have normal sensitivity to killing by a range of DNA-damaging agents, but increased SCEs following UV irradiation or mitomycin C treatments.