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Science 10 January 2003:
Vol. 299. no. 5604, pp. 259 - 262
DOI: 10.1126/science.1079447
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Reports

Dyskeratosis Congenita and Cancer in Mice Deficient in Ribosomal RNA Modification

Davide Ruggero,12 Silvia Grisendi,12 Francesco Piazza,12 Eduardo Rego,123 Francesca Mari,12 Pulivarthi H. Rao,4 Carlos Cordon-Cardo,2 Pier Paolo Pandolfi12*

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.

1 Molecular Biology Program,
2 Department of Pathology, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute, 1275 York Avenue, New York, NY 10021, USA.
3 Center for Cell-Based Therapy, FUNDHERP, University of São Paulo, Ribeirão Preto, SP 14049-900 Brazil.
4 Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
*   To whom correspondence should be addressed. E-mail: p-pandolfi{at}ski.mskcc.org

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