Specific Role for Yeast Homologs of the Diamond Blackfan Anemia-associated Rps19 Protein in Ribosome Synthesis.
Approximately 25% of cases of Diamond Blackfan anemia, a severe hypoplastic anemia, are linked to heterozygous mutations in the gene encoding ribosomal protein S19 that result in haploinsufficiency for this protein. Here we show that deletion of either of the two genes encoding Rps19 in yeast severely affects the production of 40 S ribosomal subunits. Rps19 is an essential protein that is strictly required for maturation of the 3'-end of 18 S rRNA. Depletion of Rps19 results in the accumulation of aberrant pre-40 S particles retained in the nucleus that fail to associate with pre-ribosomal factors involved in late maturation steps, including Enp1, Tsr1, and Rio2. When introduced in yeast Rps19, amino acid substitutions found in Diamond Blackfan anemia patients induce defects in the processing of the pre-rRNA similar to those observed in cells under-expressing Rps19. These results uncover a pivotal role of Rps19 in the assembly and maturation of the pre-40 S particles and demonstrate for the first time the effect of Diamond Blackfan anemia-associated mutations on the function of Rps19, strongly connecting the pathology to ribosome biogenesis.
Léger-Silvestre
Isabelle
I
Laboratoire de Biologie Moléculaire des Eucaryotes (UMR5099) and Institut d'Exploration Fonctionnelle des Génomes (IFR109), CNRS and Université Paul Sabatier, 118 route de Narbonne, 31062 Toulouse, France.
Caffrey
Jacqueline Marie
JM
Dawaliby
Rosy
R
Alvarez-Arias
Diana Alehandrovna
DA
Gas
Nicole
N
Bertolone
Salvatore J
SJ
Gleizes
Pierre-Emmanuel
PE
Ellis
Steven Robert
SR
D000483:Alleles; D000595:Amino Acid Sequence; D029503:Anemia, Diamond-Blackfan / Q000378:metabolism*; D015152:Blotting, Northern; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D005656:Fungal Proteins / Q000378:metabolism; D005690:Galactose / Q000737:chemistry; D017353:Gene Deletion; D006579:Heterozygote; D006801:Humans; D047468:Immunoprecipitation; D017404:In Situ Hybridization, Fluorescence; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000378:metabolism; D009693:Nucleic Acid Hybridization; D010957:Plasmids / Q000378:metabolism; D011132:Polyribosomes / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases; D012313:RNA / Q000737:chemistry; D012335:RNA, Ribosomal / Q000737:chemistry; D012337:RNA, Ribosomal, 18S / Q000235:genetics; D012269:Ribosomal Proteins / Q000378:metabolism / Q000502:physiology*; D012270:Ribosomes / Q000737:chemistry / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D012685:Sepharose / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D013997:Time Factors
C104527:ENP1 protein, S cerevisiae; D005656:Fungal Proteins; D009687:Nuclear Proteins; D012335:RNA, Ribosomal; D012337:RNA, Ribosomal, 18S; D012269:Ribosomal Proteins; D029701:Saccharomyces cerevisiae Proteins; C118745:TSR1 protein, Yarrowia lipolytica; C040343:ribosomal protein S19; D012313:RNA; D012685:Sepharose; D017346:Protein Serine-Threonine Kinases; C473025:Rio2 protein, S cerevisiae; D005690:Galactose