title: 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.
abstract: 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.
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RQ, UK.
authors.forename: Limei
authors.initials: L
authors.lastname: Ju
authors.forename: Jonathan
authors.initials: J
authors.lastname: Wing
authors.forename: Elaine
authors.initials: E
authors.lastname: Taylor
authors.forename: Renata
authors.initials: R
authors.lastname: Brandt
authors.forename: Predrag
authors.initials: P
authors.lastname: Slijepcevic
authors.forename: Marion
authors.initials: M
authors.lastname: Horsch
authors.forename: Birgit
authors.initials: B
authors.lastname: Rathkolb
authors.forename: Ildikó
authors.initials: I
authors.lastname: Rácz
authors.forename: Lore
authors.initials: L
authors.lastname: Becker
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hans
authors.forename: Thure
authors.initials: T
authors.lastname: Adler
authors.forename: Johannes
authors.initials: J
authors.lastname: Beckers
authors.forename: Jan
authors.initials: J
authors.lastname: Rozman
authors.forename: Martin
authors.initials: M
authors.lastname: Klingenspor
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.forename: Dirk H
authors.initials: DH
authors.lastname: Busch
authors.forename: Valérie
authors.initials: V
authors.lastname: Gailus-Durner
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.forename: Martin Hrabě
authors.initials: MH
authors.lastname: de Angelis
authors.forename: Gilbertus
authors.initials: G
authors.lastname: van der Horst
authors.forename: Alan R
authors.initials: AR
authors.lastname: Lehmann
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D020816:Amino Acid Motifs; D000818:Animals; D020134:Catalytic Domain; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D005298:Fertility / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects / Q000528:radiation effects; D020043:Genes, Essential; D018149:Glucose Intolerance / Q000235:genetics; D006410:Hematopoiesis / Q000235:genetics; D006868:Hydrolysis; D007438:Introns; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016685:Mitomycin / Q000494:pharmacology; D020125:Mutation, Missense; D059225:Nociception; D010641:Phenotype; D012854:Sister Chromatid Exchange / Q000187:drug effects / Q000528:radiation effects; D014466:Ultraviolet Rays
chemical_list: D018797:Cell Cycle Proteins; C583968:SMC6 protein, mouse; D016685:Mitomycin; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases