Autogenous Control of 5′TOP mRNA Stability by 40S Ribosomes

Mol Cell. 2017 Jul 6;67(1):55-70.e4. doi: 10.1016/j.molcel.2017.06.005. Epub 2017 Jun 29.

Abstract

Ribosomal protein (RP) expression in higher eukaryotes is regulated translationally through the 5′TOP sequence. This mechanism evolved to more rapidly produce RPs on demand in different tissues. Here we show that 40S ribosomes, in a complex with the mRNA binding protein LARP1, selectively stabilize 5′TOP mRNAs, with disruption of this complex leading to induction of the impaired ribosome biogenesis checkpoint (IRBC) and p53 stabilization. The importance of this mechanism is underscored in 5q− syndrome, a macrocytic anemia caused by a large monoallelic deletion, which we found to also encompass the LARP1 gene. Critically, depletion of LARP1 alone in human adult CD34+ bone marrow precursor cells leads to a reduction in 5′TOP mRNAs and the induction of p53. These studies identify a 40S ribosome function independent of those in translation that, with LARP1, mediates the autogenous control of 5′TOP mRNA stability, whose disruption is implicated in the pathophysiology of 5q− syndrome.

Keywords: 40S ribosomes; 5?TOP mRNAs; 5q(?) syndrome; impaired ribosome biogenesis checkpoint; p53 stabilization; polysome profiles; ribosomal proteins.

MeSH terms

  • Anemia, Macrocytic / genetics
  • Anemia, Macrocytic / metabolism
  • Autoantigens / genetics
  • Autoantigens / metabolism*
  • Bone Marrow Cells / metabolism
  • Chromosome Deletion
  • Chromosomes, Human, Pair 5 / genetics
  • Chromosomes, Human, Pair 5 / metabolism
  • HCT116 Cells
  • Humans
  • Multiprotein Complexes
  • Protein Binding
  • Protein Biosynthesis*
  • RNA 5' Terminal Oligopyrimidine Sequence*
  • RNA Interference
  • RNA Stability*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • Ribonucleoproteins / genetics
  • Ribonucleoproteins / metabolism*
  • Ribosomal Proteins / genetics
  • Ribosomal Proteins / metabolism*
  • Ribosomes / genetics
  • Ribosomes / metabolism*
  • Time Factors
  • Transfection
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Autoantigens
  • Multiprotein Complexes
  • RNA, Messenger
  • Ribonucleoproteins
  • Ribosomal Proteins
  • SS-B antigen
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • ribosomal protein L11
  • ribosomal protein L5, human

Supplementary concepts

  • Chromosome 5q Deletion Syndrome