Inactivation of the RRB1-Pescadillo pathway involved in ribosome biogenesis induces chromosomal instability.
Since chromosomal instability (CIN) is a hallmark of most cancer cells, it is essential to identify genes whose alteration results into this genetic instability. Using a yeast CIN indicator strain, we show that inactivation of the YMR131c/RRB1 gene, which is involved in early ribosome assembly and whose expression is induced when the spindle checkpoint is activated, alters chromosome segregation and blocks mitosis at the metaphase/anaphase transition. We demonstrate that RRB1 interacts with YPH1 (yeast pescadillo homologue 1) and other members of the Yph1 complex, RPL3, ERB1 and ORC6, involved in ribosome biogenesis and DNA replication. Transient depletion of the human homologues GRWD, Pescadillo, Rpl3, Bop1 and Orc6L resulted in an increase of abnormal mitoses with appearance of binucleate or hyperploid cells, of cells with multipolar spindles and of aberrant metaphase plates. If deregulation of proteins involved in ribosome biogenesis, commonly observed in malignant tumors, could contribute to cancer through an aberrant protein synthesis, our study demonstrates that alteration of proteins linking ribosome biogenesis and DNA replication may directly cause CIN.
Institut National de la Santé et de la Recherche Médicale (INSERM) U 614 - IFRMP, Faculty of Medicine, 22 Boulevard Gambetta, 76183 Rouen Cedex, France.
Audrey
A
Killian
Nathalie
N
Le Meur
Richard
R
Sesboüé
Jeannette
J
Bourguignon
Gaëlle
G
Bougeard
Julien
J
Gautherot
Christian
C
Bastard
Thierry
T
Frébourg
Jean-Michel
JM
Flaman
D000595:Amino Acid Sequence; D000705:Anaphase; D045744:Cell Line, Tumor; D043171:Chromosomal Instability; D020090:Chromosome Segregation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal; D020043:Genes, Essential / Q000235:genetics; D006801:Humans; D008677:Metaphase; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D000090822:Ribosomal Protein L3; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000235:genetics* / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D013489:Suppression, Genetic / Q000235:genetics; D013696:Temperature
D004268:DNA-Binding Proteins; C451799:NOP7 protein, S cerevisiae; D009687:Nuclear Proteins; C000716547:RPL3 protein, human; C493740:RRB1 protein, S cerevisiae; D000090822:Ribosomal Protein L3; D012269:Ribosomal Proteins; D029701:Saccharomyces cerevisiae Proteins; C429752:ribosomal protein 3