Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
ReviewStress granules, P-bodies and cancer☆
Introduction
Nascent mRNAs bind to an array of RNA-binding proteins (RBPs) and microRNAs that conspire to determine their fates. These transcripts are transported from the nucleus to the cytoplasm as a part of compositionally diverse complexes known as messenger ribonucleoprotein particles (mRNPs). The composition of these exported mRNPs determines whether transcripts are immediately translated or transported to specific subcellular regions for storage and/or localized translation. These mRNPs are also subject to quality control mechanisms that promote the degradation of transcripts that contain errors that could lead to the production of incomplete protein products (reviewed in [1], [2]).
There is an imperfect correlation between levels of mRNA and levels of the proteins they encode. Up to two-thirds of this variation can be attributed to post-transcriptional mechanisms that modulate mRNA stability and translation [3], [4]. Proteins that mediate post-transcriptional control bind to cis elements that are typically found in 5′- and 3′-untranslated regions of individual transcripts. These regulatory elements can be unique to a single RNA molecule (allowing targeted regulation of this mRNA) or be found in a subset of mRNAs encoding functionally related proteins (coordinated regulation). Individual RBPs can influence several aspects of mRNA metabolism, including mRNA decay/stabilization, subcellular localization or translation rate. The availability of these RBPs is under the control of cell-intrinsic and extracellular cues. The RBP components of RNP complexes assembled on mRNA transcripts coordinately determine mRNA stability, localization and translation to allow precise and dynamic control over protein synthesis. The reader is referred to several recent reviews on post-transcriptional regulation of gene expression by microRNAs and RBPs for more detailed information [5], [6], [7].
The intricate RBP network that regulates mRNA stability, localization and translation is spatially regulated by the assembly of stress granules and processing bodies, mRNP-containing cytoplasmic granules that influence multiple aspects of cell metabolism, especially during changing conditions. Perturbations in RNA granule functions lead to pathological phenotypes observed in multiple neurodegenerative, immunological and infectious diseases [8], [9], [10], [11]. Involvement of RNA granules in cancer initiation and progression is an emerging concept in tumor biology, and is the subject of this review.
Section snippets
Complex life of mRNA
Cytoplasmic mRNAs that pass quality control are modified with 5′-caps (m7G) and 3′-poly(A) tails that are major determinants of mRNA stability. The eukaryotic decay machinery relies on ribonucleolytic activities that remove/hydrolyze the 5′-cap structure (decapping activity) and shorten or remove the poly(A) tail (deadenylation activity) to allow 5′-3′- or 3′-5′-exonucleolytic mRNA degradation, respectively [12].
Typically, bulk mRNA decay is initiated by deadenylation [13], which is performed
Basics of stress granules and processing bodies
Although there are many types of RNA granules (e.g. stress granules (SGs), P-bodies (PBs), germ granules, neuronal granules, nuclear paraspeckles) [18], SGs and PBs are the most well understood and are closely associated with a variety of diseases including cancer. The classification of RNA granules is based on their composition (the presence of specific markers), subcellular localization (nuclear, cytoplasmic, axonal, etc.), cell of origin (germ cells, neurons), response to stimuli (stress,
Surviving the hostile cancer microenvironment: Role of RNA granules
RNA granules contain hundreds of different molecules. Their direct roles in cancer metabolism, regulation of gene expression in cancer cells, and cancer cell adaptation to tumor microenvironments are yet to be uncovered. Here, we discuss some examples of PB- and SG-associated proteins that have been implicated in cancer cell physiology.
Conclusions and perspectives
Over the past several years, substantial research has shown that RNA granules are not merely sites of mRNA storage or degradation. Instead, they are flexible and versatile regulators of gene expression, and act as signaling hubs to influence multiple aspects of cell metabolism central to carcinogenesis and metastasis. While the exact mechanisms by which RNA granules impact the development and progression of cancer are largely unknown, it is clear that the post-transcriptional mechanisms
Acknowledgments
We thank the members of the Anderson's and Ivanov's research groups for the productive discussions and helpful comments. This work was supported by National Institutes of Health grant (CA168872 and GM111700, P.A.) and a Research Development Grant from the Muscular Dystrophy Association (ID158521, P.I.) and ALS Association (N7W220, P.I.).
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This article is part of a Special Issue entitled: Translation and Cancer.