Bypass of the pre-60S ribosomal quality control as a pathway to oncogenesis.
Ribosomopathies are a class of diseases caused by mutations that affect the biosynthesis and/or functionality of the ribosome. Although they initially present as hypoproliferative disorders, such as anemia, patients have elevated risk of hyperproliferative disease (cancer) by midlife. Here, this paradox is explored using the rpL10-R98S (uL16-R98S) mutant yeast model of the most commonly identified ribosomal mutation in acute lymphoblastic T-cell leukemia. This mutation causes a late-stage 60S subunit maturation failure that targets mutant ribosomes for degradation. The resulting deficit in ribosomes causes the hypoproliferative phenotype. This 60S subunit shortage, in turn, exerts pressure on cells to select for suppressors of the ribosome biogenesis defect, allowing them to reestablish normal levels of ribosome production and cell proliferation. However, suppression at this step releases structurally and functionally defective ribosomes into the translationally active pool, and the translational fidelity defects of these mutants culminate in destabilization of selected mRNAs and shortened telomeres. We suggest that in exchange for resolving their short-term ribosome deficits through compensatory trans-acting suppressors, cells are penalized in the long term by changes in gene expression that ultimately undermine cellular homeostasis.
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742.
Sergey O
SO
Sulima
Stephanie
S
Patchett
Vivek M
VM
Advani
Kim
K
De Keersmaecker
Arlen W
AW
Johnson
Jonathan D
JD
Dinman
D063646:Carcinogenesis / Q000235:genetics*; D008958:Models, Molecular; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D000080882:Ribosomal Protein L10; D012269:Ribosomal Proteins / Q000737:chemistry / Q000235:genetics*; D054683:Ribosome Subunits, Large, Eukaryotic / Q000473:pathology*; D012270:Ribosomes / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D012441:Saccharomyces cerevisiae
D012269:Ribosomal Proteins
L10/uL16; frameshifting