title: Impaired control of IRES-mediated translation in X-linked dyskeratosis congenita.
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 Dkc1(m) 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, Dkc1(m) 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.
authors.affiliation: Human Genetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Yoon
authors.forename: Guang
authors.initials: G
authors.lastname: Peng
authors.forename: Yves
authors.initials: Y
authors.lastname: Brandenburger
authors.forename: Yves
authors.initials: Y
authors.lastname: Brandenburg
authors.forename: Ornella
authors.initials: O
authors.lastname: Zollo
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: Eduardo
authors.initials: E
authors.lastname: Rego
authors.forename: Davide
authors.initials: D
authors.lastname: Ruggero
mesh_terms: D020121:5' Untranslated Regions; D000818:Animals; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis / Q000235:genetics; D019871:Dyskeratosis Congenita / Q000235:genetics*; D006801:Humans; D007304:Insect Viruses / Q000235:genetics; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D017354:Point Mutation; D011132:Polyribosomes / Q000378:metabolism; D014176:Protein Biosynthesis; D040901:Proteomics; D011560:Pseudouridine / Q000378:metabolism; D012328:RNA Viruses / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D012335:RNA, Ribosomal / Q000378:metabolism; D014162:Transfection; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000096:biosynthesis / Q000235:genetics; D051020:bcl-X Protein / Q000096:biosynthesis / Q000235:genetics
chemical_list: D020121:5' Untranslated Regions; D018797:Cell Cycle Proteins; C112148:DKC1 protein, human; C510431:Dkc1 protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; D012335:RNA, Ribosomal; D051636:X-Linked Inhibitor of Apoptosis Protein; D051020:bcl-X Protein; D011560:Pseudouridine; D050760:Cyclin-Dependent Kinase Inhibitor p27