title: Dyskeratosis congenita and cancer in mice deficient in ribosomal RNA modification.
abstract: Mutations in DKC1 cause dyskeratosis congenita (DC), a disease characterized by premature aging and increased tumor susceptibility. The DKC1 protein binds to the box H + ACA small nucleolar RNAs and the RNA component of telomerase. Here we show that hypomorphic Dkc1 mutant (Dkc1m) mice recapitulate in the first and second generations (G1 and G2) the clinical features of DC. Dkc1m cells from G1 and G2 mice were impaired in ribosomal RNA pseudouridylation before the onset of disease. Reductions of telomere length in Dkc1m mice became evident only in later generations. These results suggest that deregulated ribosome function is important in the initiation of DC, whereas telomere shortening may modify and/or exacerbate DC.
authors.affiliation: Molecular Biology Program, Department of Pathology, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute, 1275 York Avenue, New York, NY 10021, USA.
authors.forename: Davide
authors.initials: D
authors.lastname: Ruggero
authors.forename: Silvia
authors.initials: S
authors.lastname: Grisendi
authors.forename: Francesco
authors.initials: F
authors.lastname: Piazza
authors.forename: Eduardo
authors.initials: E
authors.lastname: Rego
authors.forename: Francesca
authors.initials: F
authors.lastname: Mari
authors.forename: Pulivarthi H
authors.initials: PH
authors.lastname: Rao
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
mesh_terms: D000740:Anemia; D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000502:physiology*; D003114:Colony-Forming Units Assay; D004195:Disease Models, Animal; D019871:Dyskeratosis Congenita / Q000150:complications / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D020022:Genetic Predisposition to Disease; D006412:Hematopoietic Stem Cells / Q000502:physiology; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051379:Mice; D009154:Mutation; D009369:Neoplasms / Q000209:etiology*; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology*; D011560:Pseudouridine / Q000378:metabolism*; D012335:RNA, Ribosomal / Q000378:metabolism*; D012270:Ribosomes / Q000502:physiology; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D018797:Cell Cycle Proteins; C112148:DKC1 protein, human; D009687:Nuclear Proteins; D012335:RNA, Ribosomal; D011560:Pseudouridine; D019098:Telomerase