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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
journal contribution
posted on 2024-03-18, 10:39 authored by Limei Ju, Jonathan Wing, Elaine Taylor, Renata Brandt, Predrag Slijepcevic, Marion Horsch, Birgit Rathkolb, Ildikó Rácz, Lore Becker, Wolfgang Hans, Thure Adler, Johannes Beckers, Alan LehmannAlan Lehmann, et al.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. © 2013 Elsevier B.V.
Funding
Replication of DNA damage, and the role of the SMC5-6 protein complex in the responses to DNA damage. : MRC-MEDICAL RESEARCH COUNCIL | G0501450
Smc5/6 and replication fork stability : MRC-MEDICAL RESEARCH COUNCIL | G0901011
Structure of the Smc5-6 DNA repair and chromosome maintenance protein complex : MRC-MEDICAL RESEARCH COUNCIL | G1001668
History
Publication status
- Published
Journal
DNA RepairISSN
1568-7864Publisher
Elsevier BVPublisher URL
External DOI
Issue
5Volume
12Page range
356-366Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Institution
University of SussexPeer reviewed?
- Yes
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Keywords
Adenosine TriphosphatasesAdenosine TriphosphateAmino Acid MotifsAnimalsCatalytic DomainCell Cycle ProteinsCells, CulturedFertilityFibroblastsGenes, EssentialGlucose IntoleranceHematopoiesisHydrolysisIntronsMiceMice, Inbred C57BLMice, KnockoutMitomycinMutation, MissenseNociceptionPhenotypeSister Chromatid ExchangeUltraviolet Rays3101 Biochemistry and Cell Biology3102 Bioinformatics and Computational Biology31 Biological SciencesGeneticsBiotechnology2 Aetiology2.1 Biological and endogenous factors1 Underpinning research1.1 Normal biological development and functioningGeneric health relevance0601 Biochemistry and Cell BiologyDevelopmental Biology
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