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Adaptor proteins in long noncoding RNA biology
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Review
Adaptor proteins in long noncoding RNA biology☆ ⁎
Emily Dangelmaier, Ashish Lal
Regulatory RNAs and Cancer Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
A R T I C LE I N FO
A B S T R A C T
Keywords: lncRNA lincRNA RNA-binding protein Adaptor protein
Long noncoding RNAs (lncRNAs) are a heterogeneous class of noncoding RNAs that have gained increasing attention due to their vital roles in the regulation of diverse cellular processes. Because lncRNAs are generally expressed at low levels, are poorly conserved, and can act via diverse mechanisms, investigating the molecular mechanisms by which lncRNAs act is challenging. Similar to mRNAs, lncRNAs bind to RNA-binding proteins (RBPs) and in some cases, have been shown to regulate the activity of the RBP they bind to. Furthermore, recent studies have shown that some lncRNAs directly bind to a specific RBP that, in turn, forms a complex with other proteins that mediate the effects of the lncRNA. We termed such RBPs as adaptor proteins because they function as adaptors to recruit other proteins that indirectly associate with the lncRNA. Here, we discuss the emerging roles of adaptor proteins in lncRNA function and propose mechanistic scenarios and strategies to identify adaptor proteins that could play vital roles in the biology of a lncRNA. This article is part of a Special Issue entitled: ncRNA in control of gene expression edited by Kotb Abdelmohsen.
1. Introduction
has demonstrated that many lncRNAs play crucial roles in diverse cellular functions including transcriptional regulation, post-transcriptional regulation, epigenetic modification, nuclear organization, cell proliferation, metastasis, dosage compensation, chromosomal imprinting, and genomic stability [10–18]. Although these studies reveal that lncRNAs have significant biological functions that are often associated with diseases [19,20] and therefore represent a promising new field of research, it is becoming clear that some putative lncRNAs are translated into functional micropeptides and have been misannotated as noncoding genes [21–28]. Furthermore, many lncRNAs that are transcribed bidirectionally from promoters and enhancers may not perform sequence-specific functions, and in some cases, the act of transcription or the DNA of the lncRNA loci is responsible for the observed effect, instead of the lncRNA itself [29–31]. The most common mechanism by which lncRNAs act is most likely by interacting with RNA-binding proteins (RBPs) [14,18,32,33]. Recent evidence, including our studies, have revealed that in some cases an RBP forms a complex with other proteins to recruit such proteins to the lncRNA; we name such RBPs as adaptor proteins. Here, we discuss the role of adaptor proteins in lncRNA biology and propose mechanisms by which proteins that indirectly associate with a lncRNA via an adaptor protein could mediate lncRNA function.
The diploid human genome consists of ~2 billion bases of DNA of which < 2% (120 million bases) represents regions that code for proteins [1]. The remaining ~98% of the human genome, was historically thought to represent junk DNA. However, over the last decade, the advent of high-throughput technologies such as next-generation sequencing has made it clear that this is not the case. Approximately 50% of our noncoding DNA harbors functional repetitive sequences such as ribosomal DNA, retrotransposons and satellite DNA [2]. The remaining 50% of our noncoding DNA consists of nonrepetitive sequences including promoters, enhancers, and regions of the genome important for functional chromatin interactions [3,4]. Additionally, a significant proportion of our noncoding DNA is transcribed into long noncoding RNAs (lncRNAs), a largely unexplored class of noncoding RNAs > 200 nucleotides long [5]. The estimated number of human lncRNA genes ranges from ~16,000 predicted by GENCODE [6] to ~100,000 predicted by NONCODE [7]. The disparity between these two databases highlights both the large number of lncRNA genes in the human genome and the growing demand for reliable lncRNA research. Are most lncRNAs functional or do they represent transcriptional noise? The answer to this question is likely somewhere between these two extreme possibilities. Despite their characteristically low abundance and poor conservation outside of mammals [8,9], recent work
☆ ⁎
This article is part of a Special Issue entitled: ncRNA in control of gene expression edited by Kotb Abdelmohsen. Corresponding author. E-mail address: [email protected] (A. Lal).
https://doi.org/10.1016/j.bbagrm.2019.03.003 Received 28 January 2019; Received in revised form 27 March 2019; Accepted 28 March 2019 1874-9399/ © 2019 Published by Elsevier B.V.
Please cite this article as: Emily Dangelmaier and Ashish Lal, BBA - Gene Regulatory Mechanisms, https://doi.org/10.1016/j.bbagrm.2019.03.003
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Fig. 1. Working models on diverse functions of lncRNA-adaptor protein complexes. A lncRNA binds to an adaptor protein (an RBP), which in turn, interacts with a E3-Ubiquitin ligase (abbreviated as E3 UL) to cause protein degradation, or a histone deacetylase (abbreviated as HDAC) that removes acetyl groups from histones to alter chromatin marks or a transcription factor (abbreviated as TF) to activate its binding to the target gene promoter.
2. RNP complexes in lncRNA function: traditional RBPs and beyond
3. Proteins that indirectly associate with the lncRNA via adaptor proteins
lncRNAs act via diverse mechanisms. They can mediate their effects in cis or in trans by directly binding to DNA, RNA or proteins [34,35]. Discussing each of these scenarios is beyond the scope of this study; there are excellent reviews on this topic [13,35–38]. The most common mechanism by which lncRNAs have been shown to function is by binding to RBPs. When a lncRNA binds to an RBP, what does it do to the RBP? Conversely, what does the RBP do to the lncRNA? Although the answer to these very important mechanistic questions remains largely unclear, some studies have addressed these questions. For example, the very abundant lncRNA NORAD was found to bind to multiple molecules PUMILIO, an RBP that post-transcriptionally represses the expression of genes that promote genomic instability [14]. In the absence of NORAD, the PUMILIO proteins are free and able to bind to the mRNAs of genes encoding mitotic, DNA repair and DNA replication factors resulting in aneuploidy [14]. Thus, in this case, the lncRNA NORAD was demonstrated to regulate PUMILIO activity by soaking it up. In addition to traditional RNA-binding proteins, other proteins that modulate gene expression have domains that can bind lncRNAs [39,40]. This includes DNA-binding transcriptional regulators such as p53 [41] and WDR5 [40], as well as epigenetic factors such as PRC2 [42,43] which add or remove modifications to DNA and other regulatory proteins. Moreover, recent evidence suggests that lncRNAs can also directly bind to some transcription co-activator proteins such as the acetyltransferase enzyme CBP that associates with DNA at enhancer regions where it adds acetyl groups to histones and transcription factors to promote the recruitment of RNA polymerase II and other transcription activators and chromatin modifying proteins [44]. The authors demonstrated that binding of lncRNAs, and more specifically eRNAs, to a specific basic loop domain in CBP, resulted in the neutralization of the positive charges in this domain, which in turn, stimulated the acetyltransferase activity of CBP [44,45]. Importantly, in each of these studies, the authors identified the primary region in the protein that binds to the lncRNA.
Most noncoding RNAs operate as RNA-protein complexes, including rRNAs, snRNPs, tRNAs, microRNAs (miRNAs), telomerase and lncRNAs [46]. Although the lncRNA field has mainly focused on proteins that directly bind to the lncRNA, we propose that other proteins that do not directly bind to lncRNAs but associate with lncRNAs through proteinprotein interactions could also play a vital role in lncRNA biology. This is a viable scenario based on extensive studies on other types of noncoding RNAs such as miRNAs. For a given miRNA to post-transcriptionally repress the expression of its target mRNAs, the miRNA needs to be loaded onto a multi-protein complex called the RNA-induced silencing complex (RISC). Although the core of the RISC consists of Argonaute (Ago) and the miRNA, the functional RISC is a huge complex consisting of dozens of proteins that play important roles in gene silencing [47,48]. Thus, miRNAs serve as the perfect model in which RBPs bind proteins with catalytic activity, that in turn, mediate the effects of the miRNA. Just as miRNAs directly bind to Ago in the RISC complex and the Ago protein in turn, associates with other proteins to form a large RNP complex (the functional RISC complex), lncRNAs can bind RBPs that could function as adaptor proteins. These adaptors could interact with other proteins that may have catalytic activity through which lncRNAs can mediate their effects. To give an example, the well-studied RBP HuR, binds to several proteins of which some are important for its nuclear localization, post-translational modification, and others regulate the binding of HuR to its target mRNAs [49,50]. Given that HuR also binds to lncRNAs, we propose that some of these proteins could indirectly associate with lncRNAs via HuR, which in this case acts as an adaptor protein. An adaptor protein that binds a given lncRNA could also bind to a DNA methyltransferase (DMNT) or histone deacetylase (HDAC) via protein-protein interactions, allowing the lncRNA to regulate gene expression through epigenetic modifications or bind to a transcription factor to induce a conformational change that activates binding of the transcription factor to its target gene promoters (Fig. 1). Additionally, a given lncRNA could indirectly associate with other proteins that have enzymatic activities such as ubiquitin ligases (Fig. 1). These enzymes could associate with the lncRNA via RBPs that would act like adaptor 2
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interacting protein and the adaptor protein that is required for the formation of the protein-protein complex. The effect of these mutations on RNA pull-down experiments would further support the existence of this interaction. Finally, phenotype studies can confirm the function of this trimeric complex, where mutations that eliminate this interaction result in adverse phenotypes either in vitro or in vivo, depending on the cellular pathways that are disrupted. Hence, lncRNA-protein interactions through adaptor proteins can be easily explored experimentally.
proteins. Mechanisms of murine double minute 2 (MDM2), an E3 ubiquitin ligase that targets the major tumor suppressor protein p53 for degradation [51], further exemplify this interaction. MDM2 is bound and inhibited by the ribosomal assembly intermediate 5S RNP, which is composed of the proteins RPL5 and RPL11, and 5S rRNA, a noncoding RNA [52,53]. These components all directly bind MDM2 and are all necessary for effective MDM2 inhibition. Therefore, in this example, MDM2 is in direct contact with a noncoding RNA, but other proteins are required for this interaction to be effective. Recently, we have demonstrated that the lncRNA PURPL suppresses basal p53 levels by associating with MYBBP1A, which binds to and stabilizes p53, through the adaptor protein HuR [54]. Previous reports had shown that MYBBP1A associates with RNA even though it is not a bona fide RBP [55,56]. In our study, we found that MYBBP1A forms a protein-protein complex with HuR, and HuR recruits MYBBP1A to the lncRNA PURPL. Thus, in this case, HuR functions as an adaptor protein that recruits MYBBP1A to PURPL. Additionally, we showed in another recent study, that the RBP Matrin3, directly binds to the p53-induced lncRNA PINCR, and also associates with p53 via protein-protein interactions [57]. Therefore, in the case of the PINCR study, the adaptor protein is Matrin3. Whether Matrin3 directly binds to p53 or via other proteins, remains to be determined. In addition to our studies, it has been recently shown [58] that in breast cancer cells, specific gain-offunction mutant p53 proteins or ID4 associate with the oncogenic lncRNA MALAT1 via SRSF1, a splicing factor known to directly bind to MALAT1. The authors showed that they could pulldown MALAT1 in RNA-IP (immunoprecipitation) experiments using antibodies against p53 or ID4, when they cross-linked the cells with formaldehyde but not with UV. Because UV crosslinks only those proteins that are in direct contact with the RNA whereas formaldehyde can crosslink proteinprotein as well as protein-RNA complexes, their data suggests an indirect association of MALAT1 with mutant p53 or ID4. Thus, in this case, SRSF1 is the adaptor protein that bridges MALAT1 to mutant p53 or ID4. Together, these studies suggest that certain functions of lncRNAs may be achieved through indirect interactions with proteins that lack RNA-binding capabilities.
5. Conclusions lncRNAs are the subject of an emerging field of research that endeavors to identify the functions of these noncoding RNAs. However, the characteristically low expression levels of lncRNAs suggest that they may be transcriptional noise rather than functional biological molecules. Despite this, increasing evidence reliably demonstrates that many lncRNAs have diverse and significant functions in regulating cellular processes. This raises the question as to how lncRNAs can have important functions despite low abundance. One possibility is that lncRNAs can achieve their functions through interactions with adaptor proteins. This mechanism is well-characterized for other classifications of noncoding RNAs such as miRNAs, but a more in-depth investigation into this mechanism in lncRNAs is required. In this review, we propose that RNA-binding adaptor proteins link lncRNAs with proteins with enzymes, therein providing lncRNAs catalytic activity. Our model, which is supported by convincing evidence, explains how lncRNAs can be functional despite low expression levels and can be experimentally tested using RNA pull-downs. Thus, lncRNA association with adaptor proteins is a promising, largely unexplored mode of action that may further enlighten the functions and mechanisms of numerous lncRNAs. Transparency document The Transparency document associated this article can be found, in online version. Acknowledgments
4. Identification and characterization of adaptor proteins This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. We apologize to those whose work we were could not cite due to space limitations.
The most commonly used method to identify proteins that interact with a given lncRNA is mass spectrometry following in vitro RNA pulldowns using a biotinylated lncRNA and cell extracts [59]. However, these RNA pull-downs notoriously have a high incidence of false positives. Many of the proteins determined to associate with a lncRNA transcript of interest are not well-established nucleic acid binding proteins and thus are often eliminated from the data set. However, these “false positives” should not be ignored. This is because although they may not directly bind to the lncRNA, they could associate with an RBP that directly binds to the lncRNA and acts as an adaptor protein to recruit this protein to the lncRNA transcript. Additionally, proteins that are indirectly bound to the lncRNA could also be identified by performing mass spectrometry following lncRNA pulldowns from crosslinked cells [60,61]. Although such methods are likely to generate less false positives as compared to the in vitro RNA pull-downs, they require more material and may not be very feasible for lncRNAs that are not expressed at high levels. How can these trimeric RNP-complexes be experimentally tested? One method would involve mutating the site on the lncRNA transcript where the adaptor protein binds and then performing RNA pull-downs. If the interacting protein is present in the initial pull-downs but is absent after eliminating the binding of the adaptor protein, then the interacting protein likely interacts with the lncRNA through the adaptor protein. Additionally, co-immunoprecipitation experiments can confirm the protein-protein interaction of the interacting protein with the adaptor protein. After confirming this interaction, subsequent experiments should involve identifying and mutating the domain(s) in the
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BBA - Gene Regulatory Mechanisms journal homepage: www.elsevier.com/locate/bbagrm
Review
Adaptor proteins in long noncoding RNA biology☆ ⁎
Emily Dangelmaier, Ashish Lal
Regulatory RNAs and Cancer Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
A R T I C LE I N FO
A B S T R A C T
Keywords: lncRNA lincRNA RNA-binding protein Adaptor protein
Long noncoding RNAs (lncRNAs) are a heterogeneous class of noncoding RNAs that have gained increasing attention due to their vital roles in the regulation of diverse cellular processes. Because lncRNAs are generally expressed at low levels, are poorly conserved, and can act via diverse mechanisms, investigating the molecular mechanisms by which lncRNAs act is challenging. Similar to mRNAs, lncRNAs bind to RNA-binding proteins (RBPs) and in some cases, have been shown to regulate the activity of the RBP they bind to. Furthermore, recent studies have shown that some lncRNAs directly bind to a specific RBP that, in turn, forms a complex with other proteins that mediate the effects of the lncRNA. We termed such RBPs as adaptor proteins because they function as adaptors to recruit other proteins that indirectly associate with the lncRNA. Here, we discuss the emerging roles of adaptor proteins in lncRNA function and propose mechanistic scenarios and strategies to identify adaptor proteins that could play vital roles in the biology of a lncRNA. This article is part of a Special Issue entitled: ncRNA in control of gene expression edited by Kotb Abdelmohsen.
1. Introduction
has demonstrated that many lncRNAs play crucial roles in diverse cellular functions including transcriptional regulation, post-transcriptional regulation, epigenetic modification, nuclear organization, cell proliferation, metastasis, dosage compensation, chromosomal imprinting, and genomic stability [10–18]. Although these studies reveal that lncRNAs have significant biological functions that are often associated with diseases [19,20] and therefore represent a promising new field of research, it is becoming clear that some putative lncRNAs are translated into functional micropeptides and have been misannotated as noncoding genes [21–28]. Furthermore, many lncRNAs that are transcribed bidirectionally from promoters and enhancers may not perform sequence-specific functions, and in some cases, the act of transcription or the DNA of the lncRNA loci is responsible for the observed effect, instead of the lncRNA itself [29–31]. The most common mechanism by which lncRNAs act is most likely by interacting with RNA-binding proteins (RBPs) [14,18,32,33]. Recent evidence, including our studies, have revealed that in some cases an RBP forms a complex with other proteins to recruit such proteins to the lncRNA; we name such RBPs as adaptor proteins. Here, we discuss the role of adaptor proteins in lncRNA biology and propose mechanisms by which proteins that indirectly associate with a lncRNA via an adaptor protein could mediate lncRNA function.
The diploid human genome consists of ~2 billion bases of DNA of which < 2% (120 million bases) represents regions that code for proteins [1]. The remaining ~98% of the human genome, was historically thought to represent junk DNA. However, over the last decade, the advent of high-throughput technologies such as next-generation sequencing has made it clear that this is not the case. Approximately 50% of our noncoding DNA harbors functional repetitive sequences such as ribosomal DNA, retrotransposons and satellite DNA [2]. The remaining 50% of our noncoding DNA consists of nonrepetitive sequences including promoters, enhancers, and regions of the genome important for functional chromatin interactions [3,4]. Additionally, a significant proportion of our noncoding DNA is transcribed into long noncoding RNAs (lncRNAs), a largely unexplored class of noncoding RNAs > 200 nucleotides long [5]. The estimated number of human lncRNA genes ranges from ~16,000 predicted by GENCODE [6] to ~100,000 predicted by NONCODE [7]. The disparity between these two databases highlights both the large number of lncRNA genes in the human genome and the growing demand for reliable lncRNA research. Are most lncRNAs functional or do they represent transcriptional noise? The answer to this question is likely somewhere between these two extreme possibilities. Despite their characteristically low abundance and poor conservation outside of mammals [8,9], recent work
☆ ⁎
This article is part of a Special Issue entitled: ncRNA in control of gene expression edited by Kotb Abdelmohsen. Corresponding author. E-mail address: [email protected] (A. Lal).
https://doi.org/10.1016/j.bbagrm.2019.03.003 Received 28 January 2019; Received in revised form 27 March 2019; Accepted 28 March 2019 1874-9399/ © 2019 Published by Elsevier B.V.
Please cite this article as: Emily Dangelmaier and Ashish Lal, BBA - Gene Regulatory Mechanisms, https://doi.org/10.1016/j.bbagrm.2019.03.003
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Fig. 1. Working models on diverse functions of lncRNA-adaptor protein complexes. A lncRNA binds to an adaptor protein (an RBP), which in turn, interacts with a E3-Ubiquitin ligase (abbreviated as E3 UL) to cause protein degradation, or a histone deacetylase (abbreviated as HDAC) that removes acetyl groups from histones to alter chromatin marks or a transcription factor (abbreviated as TF) to activate its binding to the target gene promoter.
2. RNP complexes in lncRNA function: traditional RBPs and beyond
3. Proteins that indirectly associate with the lncRNA via adaptor proteins
lncRNAs act via diverse mechanisms. They can mediate their effects in cis or in trans by directly binding to DNA, RNA or proteins [34,35]. Discussing each of these scenarios is beyond the scope of this study; there are excellent reviews on this topic [13,35–38]. The most common mechanism by which lncRNAs have been shown to function is by binding to RBPs. When a lncRNA binds to an RBP, what does it do to the RBP? Conversely, what does the RBP do to the lncRNA? Although the answer to these very important mechanistic questions remains largely unclear, some studies have addressed these questions. For example, the very abundant lncRNA NORAD was found to bind to multiple molecules PUMILIO, an RBP that post-transcriptionally represses the expression of genes that promote genomic instability [14]. In the absence of NORAD, the PUMILIO proteins are free and able to bind to the mRNAs of genes encoding mitotic, DNA repair and DNA replication factors resulting in aneuploidy [14]. Thus, in this case, the lncRNA NORAD was demonstrated to regulate PUMILIO activity by soaking it up. In addition to traditional RNA-binding proteins, other proteins that modulate gene expression have domains that can bind lncRNAs [39,40]. This includes DNA-binding transcriptional regulators such as p53 [41] and WDR5 [40], as well as epigenetic factors such as PRC2 [42,43] which add or remove modifications to DNA and other regulatory proteins. Moreover, recent evidence suggests that lncRNAs can also directly bind to some transcription co-activator proteins such as the acetyltransferase enzyme CBP that associates with DNA at enhancer regions where it adds acetyl groups to histones and transcription factors to promote the recruitment of RNA polymerase II and other transcription activators and chromatin modifying proteins [44]. The authors demonstrated that binding of lncRNAs, and more specifically eRNAs, to a specific basic loop domain in CBP, resulted in the neutralization of the positive charges in this domain, which in turn, stimulated the acetyltransferase activity of CBP [44,45]. Importantly, in each of these studies, the authors identified the primary region in the protein that binds to the lncRNA.
Most noncoding RNAs operate as RNA-protein complexes, including rRNAs, snRNPs, tRNAs, microRNAs (miRNAs), telomerase and lncRNAs [46]. Although the lncRNA field has mainly focused on proteins that directly bind to the lncRNA, we propose that other proteins that do not directly bind to lncRNAs but associate with lncRNAs through proteinprotein interactions could also play a vital role in lncRNA biology. This is a viable scenario based on extensive studies on other types of noncoding RNAs such as miRNAs. For a given miRNA to post-transcriptionally repress the expression of its target mRNAs, the miRNA needs to be loaded onto a multi-protein complex called the RNA-induced silencing complex (RISC). Although the core of the RISC consists of Argonaute (Ago) and the miRNA, the functional RISC is a huge complex consisting of dozens of proteins that play important roles in gene silencing [47,48]. Thus, miRNAs serve as the perfect model in which RBPs bind proteins with catalytic activity, that in turn, mediate the effects of the miRNA. Just as miRNAs directly bind to Ago in the RISC complex and the Ago protein in turn, associates with other proteins to form a large RNP complex (the functional RISC complex), lncRNAs can bind RBPs that could function as adaptor proteins. These adaptors could interact with other proteins that may have catalytic activity through which lncRNAs can mediate their effects. To give an example, the well-studied RBP HuR, binds to several proteins of which some are important for its nuclear localization, post-translational modification, and others regulate the binding of HuR to its target mRNAs [49,50]. Given that HuR also binds to lncRNAs, we propose that some of these proteins could indirectly associate with lncRNAs via HuR, which in this case acts as an adaptor protein. An adaptor protein that binds a given lncRNA could also bind to a DNA methyltransferase (DMNT) or histone deacetylase (HDAC) via protein-protein interactions, allowing the lncRNA to regulate gene expression through epigenetic modifications or bind to a transcription factor to induce a conformational change that activates binding of the transcription factor to its target gene promoters (Fig. 1). Additionally, a given lncRNA could indirectly associate with other proteins that have enzymatic activities such as ubiquitin ligases (Fig. 1). These enzymes could associate with the lncRNA via RBPs that would act like adaptor 2
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interacting protein and the adaptor protein that is required for the formation of the protein-protein complex. The effect of these mutations on RNA pull-down experiments would further support the existence of this interaction. Finally, phenotype studies can confirm the function of this trimeric complex, where mutations that eliminate this interaction result in adverse phenotypes either in vitro or in vivo, depending on the cellular pathways that are disrupted. Hence, lncRNA-protein interactions through adaptor proteins can be easily explored experimentally.
proteins. Mechanisms of murine double minute 2 (MDM2), an E3 ubiquitin ligase that targets the major tumor suppressor protein p53 for degradation [51], further exemplify this interaction. MDM2 is bound and inhibited by the ribosomal assembly intermediate 5S RNP, which is composed of the proteins RPL5 and RPL11, and 5S rRNA, a noncoding RNA [52,53]. These components all directly bind MDM2 and are all necessary for effective MDM2 inhibition. Therefore, in this example, MDM2 is in direct contact with a noncoding RNA, but other proteins are required for this interaction to be effective. Recently, we have demonstrated that the lncRNA PURPL suppresses basal p53 levels by associating with MYBBP1A, which binds to and stabilizes p53, through the adaptor protein HuR [54]. Previous reports had shown that MYBBP1A associates with RNA even though it is not a bona fide RBP [55,56]. In our study, we found that MYBBP1A forms a protein-protein complex with HuR, and HuR recruits MYBBP1A to the lncRNA PURPL. Thus, in this case, HuR functions as an adaptor protein that recruits MYBBP1A to PURPL. Additionally, we showed in another recent study, that the RBP Matrin3, directly binds to the p53-induced lncRNA PINCR, and also associates with p53 via protein-protein interactions [57]. Therefore, in the case of the PINCR study, the adaptor protein is Matrin3. Whether Matrin3 directly binds to p53 or via other proteins, remains to be determined. In addition to our studies, it has been recently shown [58] that in breast cancer cells, specific gain-offunction mutant p53 proteins or ID4 associate with the oncogenic lncRNA MALAT1 via SRSF1, a splicing factor known to directly bind to MALAT1. The authors showed that they could pulldown MALAT1 in RNA-IP (immunoprecipitation) experiments using antibodies against p53 or ID4, when they cross-linked the cells with formaldehyde but not with UV. Because UV crosslinks only those proteins that are in direct contact with the RNA whereas formaldehyde can crosslink proteinprotein as well as protein-RNA complexes, their data suggests an indirect association of MALAT1 with mutant p53 or ID4. Thus, in this case, SRSF1 is the adaptor protein that bridges MALAT1 to mutant p53 or ID4. Together, these studies suggest that certain functions of lncRNAs may be achieved through indirect interactions with proteins that lack RNA-binding capabilities.
5. Conclusions lncRNAs are the subject of an emerging field of research that endeavors to identify the functions of these noncoding RNAs. However, the characteristically low expression levels of lncRNAs suggest that they may be transcriptional noise rather than functional biological molecules. Despite this, increasing evidence reliably demonstrates that many lncRNAs have diverse and significant functions in regulating cellular processes. This raises the question as to how lncRNAs can have important functions despite low abundance. One possibility is that lncRNAs can achieve their functions through interactions with adaptor proteins. This mechanism is well-characterized for other classifications of noncoding RNAs such as miRNAs, but a more in-depth investigation into this mechanism in lncRNAs is required. In this review, we propose that RNA-binding adaptor proteins link lncRNAs with proteins with enzymes, therein providing lncRNAs catalytic activity. Our model, which is supported by convincing evidence, explains how lncRNAs can be functional despite low expression levels and can be experimentally tested using RNA pull-downs. Thus, lncRNA association with adaptor proteins is a promising, largely unexplored mode of action that may further enlighten the functions and mechanisms of numerous lncRNAs. Transparency document The Transparency document associated this article can be found, in online version. Acknowledgments
4. Identification and characterization of adaptor proteins This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. We apologize to those whose work we were could not cite due to space limitations.
The most commonly used method to identify proteins that interact with a given lncRNA is mass spectrometry following in vitro RNA pulldowns using a biotinylated lncRNA and cell extracts [59]. However, these RNA pull-downs notoriously have a high incidence of false positives. Many of the proteins determined to associate with a lncRNA transcript of interest are not well-established nucleic acid binding proteins and thus are often eliminated from the data set. However, these “false positives” should not be ignored. This is because although they may not directly bind to the lncRNA, they could associate with an RBP that directly binds to the lncRNA and acts as an adaptor protein to recruit this protein to the lncRNA transcript. Additionally, proteins that are indirectly bound to the lncRNA could also be identified by performing mass spectrometry following lncRNA pulldowns from crosslinked cells [60,61]. Although such methods are likely to generate less false positives as compared to the in vitro RNA pull-downs, they require more material and may not be very feasible for lncRNAs that are not expressed at high levels. How can these trimeric RNP-complexes be experimentally tested? One method would involve mutating the site on the lncRNA transcript where the adaptor protein binds and then performing RNA pull-downs. If the interacting protein is present in the initial pull-downs but is absent after eliminating the binding of the adaptor protein, then the interacting protein likely interacts with the lncRNA through the adaptor protein. Additionally, co-immunoprecipitation experiments can confirm the protein-protein interaction of the interacting protein with the adaptor protein. After confirming this interaction, subsequent experiments should involve identifying and mutating the domain(s) in the
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