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Science 312 (5775): 902-906

Copyright © 2006 by the American Association for the Advancement of Science

Impaired Control of IRES-Mediated Translation in X-Linked Dyskeratosis Congenita

Andrew Yoon,1* Guang Peng,1* Yves Brandenburg,1* Ornella Zollo,1 Wei Xu,1 Eduardo Rego,2 Davide Ruggero1{dagger}

Abstract: The DKC1 gene encodes a pseudouridine synthase that modifies ribosomal RNA (rRNA). DKC1 is mutated in people with X-linked dyskeratosis congenita (X-DC), a disease characterized by bone marrow failure, skin abnormalities, and increased susceptibility to cancer. How alterations in ribosome modification might lead to cancer and other features of the disease remains unknown. Using an unbiased proteomics strategy, we discovered a specific defect in IRES (internal ribosome entry site)–dependent translation in Dkc1m mice and in cells from X-DC patients. This defect results in impaired translation of messenger RNAs containing IRES elements, including those encoding the tumor suppressor p27(Kip1) and the antiapoptotic factors Bcl-xL and XIAP (X-linked Inhibitor of Apoptosis Protein). Moreover, Dkc1m ribosomes were unable to direct translation from IRES elements present in viral messenger RNAs. These findings reveal a potential mechanism by which defective ribosome activity leads to disease and cancer.

1 Human Genetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
2 Center for Cell Based Therapy, Fundação Hemocentro de Ribeirão Preto, University of Sao Paulo, Brazil.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: davide.ruggero{at}fccc.edu


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