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: Davide Ruggero, Silvia Grisendi, Francesco Piazza, Eduardo Rego, Francesca Mari, Pulivarthi H Rao, Carlos Cordon-Cardo, Pier Paolo Pandolfi
• Journal: Science (New York, N.Y.) (Science) Vol. 299 Issue 5604 Pg. 259-62 (Jan 10 2003) ISSN: 1095-9203 [Electronic] United States
• PMID: 12522253 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• DKC1 protein, human
• Nuclear Proteins
• RNA, Ribosomal
• Pseudouridine
• Telomerase

Topics

• Anemia
• Animals
• Apoptosis
• Bone Marrow Cells
• Cell Cycle Proteins (genetics, physiology)
• Colony-Forming Units Assay
• Disease Models, Animal
• Dyskeratosis Congenita (complications, genetics, metabolism)
• Female
• Genetic Predisposition to Disease
• Hematopoietic Stem Cells (physiology)
• In Situ Hybridization, Fluorescence
• Male
• Mice
• Mutation
• Neoplasms (etiology)
• Nuclear Proteins (genetics, physiology)
• Pseudouridine (metabolism)
• RNA, Ribosomal (metabolism)
• Ribosomes (physiology)
• Telomerase (metabolism)
• Telomere (metabolism, ultrastructure)