Stressing out Over Long Noncoding RNA☆

Biochimica et Biophysica Acta 1859 (2016) 184–191 Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbagrm Review Stressing out over long noncoding RNA☆ Timothy E. Audas, Stephen Lee ⁎ Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA article info abstract Article history: Genomic studies have revealed that humans possess far fewer protein-encoding genes than originally predicted. Received 2 April 2015 These over-estimates were drawn from the inherent developmental and stimuli-responsive complexity found in Received in revised form 17 June 2015 humans and other mammals, when compared to lower eukaryotic organisms. This left a conceptual void in many Accepted 19 June 2015 cellular networks, as a new class of functional molecules was necessary for “fine-tuning” the basic proteomic Available online 2 July 2015 machinery. Transcriptomics analyses have determined that the vast majority of the genetic material is tran- Keywords: scribed as noncoding RNA, suggesting that these molecules could provide the functional diversity initially sought Long noncoding RNA from proteins. Indeed, as discussed in this review, long noncoding RNAs (lncRNAs), the largest family of noncod- Stress Response ing transcripts, have emerged as common regulators of many cellular stressors; including heat shock, metabolic Cancer deprivation and DNA damage. These stimuli, while divergent in nature, share some common stress-responsive pathways, notably inhibition of cell proliferation. This role intrinsically makes stress-responsive lncRNA regulators potential tumor suppressor or proto-oncogenic genes. As the list of functional RNA molecules continues to rapidly expand it is becoming increasingly clear that the significance and functionality of this family may someday rival that of proteins. This article is part of a Special Issue entitled: Clues to long noncoding RNA taxon- omy1, edited by Dr. Tetsuro Hirose and Dr. Shinichi Nakagawa. © 2015 Elsevier B.V. All rights reserved. 1. Introduction have revealed that only 2% of the genetic material contains protein- encoding sequences [5,6]. Additionally, humans, chickens, pufferfish and It is a mystery why it has taken so long for the scientific community to worms share a similar number of protein-encoding genes [7–12], leaving embrace the concept of functional RNA molecules. The existence of these a conceptual void in the increased developmental complexity and envi- transcripts was proposed by Francis Crick in the 1950s, when he hypoth- ronmental adaptability found in the higher organisms [13,14]. This sug- esized about “metabolic RNA”,despite“meager” evidence at the time to gests that the capacity to regulate organismal complexity may fall to support his notion [1]. The proof he sought arrived only a few years another class of molecules. The RNA transcriptome appears to be a later with the identification of the first noncoding RNAs: transfer RNA prime candidate to accomplish this task, as studies have shown that the (tRNA), ribosomal RNA (rRNA) and small nuclear RNA (snRNA) [2,3]. vast majority of the genome is actively transcribed [15].Longnoncoding These transcripts were shown to be prominent and indispensable factors RNAs (lncRNAs) represent the single largest family of non-protein- in their ribonucleoprotein complexes. Unfortunately, their discoveries did coding transcripts in mammals (70–90% of the human genome) [16]. not usher in an era of acceptance of RNA as functional ribozymes; instead This enormous group of molecules has been arbitrarily lumped together the central dogma of gene expression [4] remained for many decades, (lengths greater than 200 nucleotides), with some sub-categories emerg- with every basic biology class teaching that DNA codes for RNA that ing based on the location of the gene with respect to protein-encoding codes for proteins. This ensured that for several generations, scientists loci. However, this system appears to be insufficient as more transcripts would view RNA as a mere messenger for the genetic material. are identified and characterized, revealing a diversity for this group that Today noncoding RNAs are emerging as important biological mole- may eventually rival or surpass the proteome. Given their novelty, func- cules, outside of the context of protein synthesis. The classic proteo- tionality and sheer abundance, it is clear that lncRNAs are destined to centric view of polypeptides as the predominant functional and regulatory have a tremendous impact on many areas of cell biology. factors within the cell may in fact be faulty. Genome sequencing results 2. The cellular response to stress ☆ This article is part of a Special Issue entitled: Clues to long noncoding RNA taxonomy1, edited by Dr. Tetsuro Hirose and Dr. Shinichi Nakagawa. One emerging field in lncRNA biology is deciphering the role these ⁎ Corresponding author at: Department of Biochemistry & Molecular Biology, Sylvester transcripts play in the cellular response to stress. Higher eukaryotes Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33101-6129, USA. possess extremely sophisticated molecular networks to monitor intra- E-mail address: [email protected] (S. Lee). and extra-cellular conditions and allow cells to maintain homeostasis http://dx.doi.org/10.1016/j.bbagrm.2015.06.010 1874-9399/© 2015 Elsevier B.V. All rights reserved. T.E. Audas, S. Lee / Biochimica et Biophysica Acta 1859 (2016) 184–191 185 in suboptimal growth environments. Perturbation activates these path- pathwaysareactivatedbythepresenceofdamaged,unfoldedoraggre- ways, as the cell attempts to mitigate the strain and repair any gated proteins, which is a major consequence of elevated temperatures. associated damages. However, if these conditions are too harsh for To alleviate this form of proteotoxic stress cells: 1) induce the expression recovery to occur apoptotic programs are induced, eliminating dam- of heat shock proteins (hsp), a family of proteases and chaperones, 2) aged cells and ensuring organismal viability. The pro-survival or pro- inhibit the transcription/translation of proteins, thus reducing the burden apoptotic fate of a cell is entirely dependent upon its ability to elicit on the folding machinery and 3) impair major metabolic activities includ- the appropriate response to the specific stimuli. Recent evidence ing; RNA splicing, nucleo-cytoplasmic transport and DNA synthesis to suggests that lncRNAs are key factors in these pathways, allowing for focus the cellular energy/resources on stress recovery [19–21]. All of greater diversity and “fine tuning” of the cellular stress response. these pathways utilize lncRNA to elicit the appropriate response. Within an organism, individual cells can be exposed to numerous adverse conditions including: high temperatures (proteotoxic stress), metabolite deprivation (nutrient deficiency and hypoxia) and DNA 3.1. Induction of heat shock proteins damaging agents. Regardless of the detrimental stimulus, the cellular response follows a basic three step process: sense the insult, transduce The lncRNA molecule heat shock RNA-1 (HSR-1) has been suggested a signal to the site of action and effect the appropriate adjustments to to be an important factor in the ribonucleoprotein complex that acti- cellular metabolism [17]. Here, we will review these environmental vates the hsp family in response to heat shock [22]. In cooperation stimuli and highlight the essential roles lncRNAs play in regulating the with three molecules of heat shock transcription factor-1 (HSF-1) and cellular stress response (Table 1). For the sake of space we will limit the translation elongation factor eEF1A, the HSR-1 complex binds DNA our review primarily to mammalian lncRNAs and analyzing the effects responsive elements to activate gene expression [22]. The authors proof these transcripts in human cancers. posed that this lncRNA may act as a mammalian RNA thermosensor, regulating the activity of the complex. While the work on HSR-1 has 3. The lncRNA-mediated heat shock response been called into question (some suggest this lncRNA is the product of bacterial contamination [23]), the concept of RNA thermosensors is in- Many consider high temperature exposure, termed heat shock, to be triguing. Bacterial and drosophila mRNAs have been shown to possess the founding and preeminent cellular stress [18]. Not surprisingly, the thermo-sensitive base-pairing in the untranscribed regions of some cell does not appear to possess a simple thermostat, detecting unaccept- mRNA, which regulate the rate of translation of these molecules able temperature and eliciting a cellular response. Instead, heat shock [24–31]. As the secondary structure of noncoding RNA molecules is Table 1 Examples of long noncoding RNAs associated with stress and cancer. Stimulus lncRNA lncRNA response to stress Function Linked to References cancer HSR-1 No change in RNA levels Complex with HSF-1 and eEF1A to activate hsp genes No [22] (acts as a thermosensor?) – Heat shock Alu Up-regulation Inhibit global RNA Pol II transcription No [34 40] Sat III Up-regulation Inhibition of global RNA processing by sequestration No [50–58] of RNA splicing components into nuclear stress bodies IGSRNA Up-regulation (stress-specific Protein immobilization in the nucleolar detention center No [62–67] IGSRNAs are

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