Nucleolar stress: Molecular mechanisms and related human diseases

Abstract

Ribosome biogenesis in the nucleolus is an important process that consumes 80% of a cell's intracellular energy supply. Disruption of this process results in nucleolar stress, triggering the activation of molecular systems that respond to this stress to maintain homeostasis. Although nucleolar stress was originally thought to be caused solely by abnormalities of ribosomal RNA (rRNA) and ribosomal proteins (RPs), an accumulating body of more current evidence suggests that many other factors, including the DNA damage response and oncogenic stress, are also involved in nucleolar stress response signaling. Cells reacting to nucleolar stress undergo cell cycle arrest or programmed death, mainly driven by activation of the tumor suppressor p53. This observation has nominated nucleolar stress as a promising target for cancer therapy. However, paradoxically, some RP mutations have also been implicated in cancer initiation and progression, necessitating caution. In this article, we summarize recent findings on the molecular mechanisms of nucleolar stress and the human ribosomal diseases and cancers that arise in its wake.

Keywords: PICT1; RPL11; nucleolar stress; p53; ribosomal disease; signal transduction.

FIGURE 1

Mechanisms of ribosome biogenesis and triggers of nucleolar stress. Normal ribosome biogenesis starts in the nucleolus via three initial steps (shown in blue): (i) Pol I–mediated transcription of a large rRNA precursor (pre‐rRNA) and Pol III–mediated transcription of a smaller rRNA precursor that constitutes the 5S subunit; (ii) processing of the large rRNA precursor into 18S, 5.8S, and 28S mature rRNAs; (iii) assembly of the 18S subunit with 33 types of RPS to form the pre‐40S ribosome particle, and assembly of the 5.8S, 28S, and 5S subunits with 48 types of large ribosomal subunit protein (RPL) to form the pre‐60S ribosome particle. The pre‐40S and pre‐60S ribosome particles are then exported from the nucleolus through the nucleoplasm into the cytoplasm, where they combine to form mature 80S ribosomes. It is the 80S ribosomes that take up mRNA and translate it into protein. Insults that cause nucleolar stress, for example, those which interfere with steps (i)‐(iii) above during early ribosome biogenesis, are listed in red text

FIGURE 2

p53‐dependent nucleolar stress response pathways. Nucleolar stress induces the translocation of the nucleolar proteins indicated in the red dotted box into the nucleoplasm. These proteins then stabilize p53 by the various indicated processes (see main text for details). Cells with elevated p53 then undergo cell cycle arrest and/or cell death

FIGURE 3

p53‐independent nucleolar stress response pathways. Nucleolar stress induces the translocation of the nucleolar proteins indicated in the dotted boxes into the nucleoplasm or cytoplasm, where they trigger cell cycle arrest and/or cell death through the inhibition of NFκB, CBS, E2F‐1, or MYC or the activation of BAX (see main text for details)

FIGURE 4

Nucleolar stress and human ribosomal diseases. During normal ribosome biogenesis, ribosomal proteins (RPs) are assembled with rRNAs (transcribed and processed) to form pre‐ribosomes, which then combine to produce mature ribosomes. Any abnormality in this sequence of events stabilizes and activates p53. In blue text are human diseases whose molecular defects affect ribosome biogenesis at the indicated stage. p53 is also stabilized when NPM1 abnormally translocates from the nucleolus into the nucleoplasm, an effect associated with Zika virus infection, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) (see main text for details)

FIGURE 5

Nucleolar stress and cancer. Mutations in ribosomal proteins (RPs) and Shwachman‐Bodian‐Diamond syndrome ribosome maturation factor (SBDS) may alter ribosome function, which induces nucleolar stress and p53 activation. Although this p53 activation attempts to block tumorigenesis, the altered ribosome function may lead to increased translation of oncogenes and decreased translation of tumor suppressors, all of which promote cancer. These mutations also reduce superoxide dismutase‐2 (SOD2) activity and promote reactive oxygen species (ROS) production, which may activate PI3K/MAPK signaling supporting cancer development. ROS also trigger DNA damage, which contributes to tumor formation on one hand but also activates tumor suppression by p53 on the other hand. When these cell‐proliferative and deleterious events combine to overcome p53 signaling mediating tumor suppression, cancer starts to develop. In contrast, novel types of drugs that can inhibit ribosome biogenesis and induce nucleolar stress without triggering DNA damage or excessive ROS may activate p53 sufficiently to suppress tumorigenesis. These agents could represent a fresh avenue of anticancer therapy (see main text for details)