Ribosomopathies: how a common root can cause a tree of pathologies.
Phenotypes of ribosomopathies are mediated both by p53-dependent and -independent pathways.The current challenge is to identify differences in response to ribosomal stress that lead to specific tissue defects in various ribosomopathies.Here, we review recent findings in this field, with a particular focus on animal models, and discuss how, in some cases, the different phenotypes of ribosomopathies might arise from differences in the spatiotemporal expression of the affected genes.
Affiliation: Department of Molecular, Cell & Developmental Biology, University of California, Los Angeles, CA 90095, USA firstname.lastname@example.org email@example.com.
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DMM020529F3: Defects in ribosomal biogenesis activate p53 and other stress-response mechanisms. A schematic showing pre-rRNA transcription, and assembly of accessory factors and RPs on the nascent pre-rRNA. (A) Recent studies have suggested that problems with pre-rRNA processing can affect DNA transcription, leading to the activation of ATR-ATM-Chk1/2 signaling (which is responsible for the replication-stress and DNA-damage checkpoints) and p53 upregulation. In addition, deoxynucleoside triphosphate (dNTP) imbalance caused by RP deficiency might interfere with transcription and replication and contribute to ATR-ATM activation. (B) Problems with pre-RNA processing compromise ribosome biogenesis and lead to nucleolar disruption. The nucleolus is involved in maintaining low p53 levels by exporting it for degradation. Various stressors disrupt nucleolar organization, compromising p53 export and leading to p53 accumulation in the nucleus. Nucleolar disruption might also lead to the release of factors that activate p53 or cause cell cycle arrest by p53-independent mechanisms. (C) An alternative pathway of p53 activation is through free RPs that, in complex with 5S RNA, bind the p53 negative regulator MDM2, releasing p53 from its control. (D) Upregulation of MYC and RAS pro-survival factors in DBA patients and in animal models suggests that they might activate p14ARF, which, in complex with 5S RNA, also negatively regulates MDM2. Hypothetically, additional not-yet-identified nucleolar factors might also negatively interact with MDM2 and contribute to p53 upregulation. (E) p53 might also be activated by secondary changes in RP-deficient cells, such as increased levels of ROS or decreased levels of ATP, which activates AMPK, which, in turn, activates p53. p53 then translocates to the nucleus. (F) p53 activation leads to cell cycle arrest and to the induction of downstream pathways ranging from cellular repair to apoptotic mechanisms. (G) A p53-independent response might also originate from the cytoplasm owing to a decreased number and altered activity of ribosomes, which also can lead to cell cycle arrest. For example, decreased levels of cyclins or PIM1 caused by RP deficiency might inhibit cell cycle progression. Abbreviations: AMPK, AMP-activated protein kinase; ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia and Rad3 related; Chk1/2, checkpoint kinase 1/2; MDM2, MDM2 oncogene, E3 ubiquitin protein ligase; MYC, avian myelocytomatosis viral oncogene homolog; p14ARF, alternate reading frame protein product of the CDKN2A, cyclin-dependent kinase inhibitor 2A; PIM, pim-1 oncogene; PolI, RNA polymerase I; RAS, rat sarcoma viral oncogene homolog; ROS, reactive oxygen species; 5S, rRNA. See Fig. 2 for a key.
One way in which altered ribosome biogenesis might affect p53 is through RPs that are not incorporated into ribosomes (Fig. 3). Several RPs have been shown to bind Mdm2 (mouse double minute 2 homolog, which is a negative regulator of p53) and to inhibit its binding to p53, leading to p53 stabilization and to cell cycle arrest (Zhang and Lu, 2009). Attaining the right balance between the synthesis of rRNA and RPs seems to be important; when rRNA synthesis is decreased, RPs are no longer used for ribosome building and can stabilize p53 (Donati et al., 2011). Thus, p53 stabilization by RPs might be a general mechanism involved in the response to various stresses.Fig. 3.