title: SirT1 catalytic activity is required for male fertility and metabolic homeostasis in mice.
abstract: The protein encoded by the sirt1 gene is an enzyme, SirT1, that couples the hydrolysis of NAD(+) to the deacetylation of acetyl-lysine residues in substrate proteins. Mutations of the sirt1 gene that fail to encode protein have been introduced into the mouse germ line, and the animals homozygous for these null mutations have various physiological abnormalities. To determine which of the characteristics of these sirt1(-/-) mice are a consequence of the absence of the catalytic activity of the SirT1 protein, we created a mouse strain carrying a point mutation (H355Y) that ablates the catalytic activity but does not affect the amount of the SirT1 protein. Mice carrying point mutations in both sirt1 genes, sirt1(Y/Y), have a phenotype that is overlapping but not identical to that of the sirt1-null animals. The sirt1(Y/Y) phenotype is significantly milder than that seen in the sirt1(-/-) animals. For example, female sirt1(Y/Y) animals are fertile, while sirt1(-/-) females are sterile. On the other hand, both sirt1(-/-) and sirt1(Y/Y) male mice are sterile and hypermetabolic. We report that sirt1(Y/Y) mice respond aberrantly to caloric restriction, although the effects are more subtle than seen in sirt1(-/-) mice. Thus, the SirT1 protein has functions that can be attributed to the catalytic activity of the protein, as well as other functions that are conferred by the protein itself.
authors: Program for Cancer Therapeutics, Ottawa Hospital Research Institute, Otttawa, Ontario, Canada.
authors: Erin L
authors: EL
authors: Seifert
authors: Annabelle Z
authors: AZ
authors: Caron
authors: Katy
authors: K
authors: Morin
authors: Josée
authors: J
authors: Coulombe
authors: Xiao Hong
authors: XH
authors: He
authors: Karen
authors: K
authors: Jardine
authors: Danielle
authors: D
authors: Dewar-Darch
authors: Kim
authors: K
authors: Boekelheide
authors: Mary-Ellen
authors: ME
authors: Harper
authors: Michael W
authors: MW
authors: McBurney
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D031204:Caloric Restriction; D017124:Conserved Sequence; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005298:Fertility / Q000235:genetics / Q000502:physiology*; D006639:Histidine / Q000737:chemistry; D006706:Homeostasis; D007248:Infertility, Male / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009043:Motor Activity / Q000235:genetics / Q000502:physiology; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D017354:Point Mutation; D011247:Pregnancy; D056564:Sirtuin 1 / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013091:Spermatogenesis / Q000235:genetics / Q000502:physiology
chemical_list: D017931:DNA Primers; D050505:Mutant Proteins; D006639:Histidine; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1