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 ( Dkc1 ^m ) mice recapitulate in the first and second generations (G1 and G2) the clinical features of DC. Dkc1 ^m cells from G1 and G2 mice were impaired in ribosomal RNA pseudouridylation before the onset of disease. Reductions of telomere length in Dkc1 ^m 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.