title: The mammalian SIR2alpha protein has a role in embryogenesis and gametogenesis.
abstract: The yeast Sir2p protein has an essential role in maintaining telomeric and mating type genes in their transcriptionally inactive state. Mammalian cells have a very large proportion of their genome inactive and also contain seven genes that have regions of homology with the yeast sir2 gene. One of these mammalian genes, sir2alpha, is the presumptive mammalian homologue of the yeast sir2 gene. We set out to determine if sir2alpha plays a role in mammalian gene silencing by creating a strain of mice carrying a null allele of sir2alpha. Animals carrying two null alleles of sir2alpha were smaller than normal at birth, and most died during the early postnatal period. In an outbred background, the sir2alpha null animals often survived to adulthood, but both sexes were sterile. We found no evidence for failure of gene silencing in sir2alpha null animals, suggesting that either SIR2alpha has a different role in mammals than it does in Saccharomyces cerevisiae or that its role in gene silencing in confined to a small subset of mammalian genes. The phenotype of the sir2alpha null animals suggests that the SIR2alpha protein is essential for normal embryogenesis and for normal reproduction in both sexes.
authors.affiliation: Ottawa Regional Cancer Centre and Department of Medicine, University of Ottawa, Ontario K1H 1C4, Canada. michael.mcburney@orcc.on.ca
authors.forename: Michael W
authors.initials: MW
authors.lastname: McBurney
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Yang
authors.forename: Karen
authors.initials: K
authors.lastname: Jardine
authors.forename: Mary
authors.initials: M
authors.lastname: Hixon
authors.forename: Kim
authors.initials: K
authors.lastname: Boekelheide
authors.forename: John R
authors.initials: JR
authors.lastname: Webb
authors.forename: Peter M
authors.initials: PM
authors.lastname: Lansdorp
authors.forename: Madeleine
authors.initials: M
authors.lastname: Lemieux
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D021461:Animals, Outbred Strains; D004622:Embryo, Mammalian / Q000502:physiology*; D022041:Euchromatin / Q000235:genetics / Q000378:metabolism; D005260:Female; D005313:Fetal Death / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D005854:Germ Cells / Q000502:physiology*; D007247:Infertility, Female / Q000235:genetics; D007248:Infertility, Male / Q000235:genetics; D008297:Male; D008322:Mammals; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics* / Q000378:metabolism*; D016615:Telomere / Q000235:genetics; D013737:Testis / Q000002:abnormalities / Q000502:physiology
chemical_list: D022041:Euchromatin; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins