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Cancer Theâ•Ÿrbpâ•Žeutics-RNA-Binding Proteins As Pharmacology & Therapeutics 203 (2019) 107390 Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Cancer the‘RBP’eutics–RNA-binding proteins as therapeutic targets for cancer Shakur Mohibi, Xinbin Chen, Jin Zhang ⁎ Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of California at Davis, United States article info abstract Available online 11 July 2019 RNA-binding proteins (RBPs) play a critical role in the regulation of various RNA processes, including splicing, cleavage and polyadenylation, transport, translation and degradation of coding RNAs, non-coding RNAs and Keywords: microRNAs. Recent studies indicate that RBPs not only play an instrumental role in normal cellular processes RNA-binding proteins but have also emerged as major players in the development and spread of cancer. Herein, we review the current RNA-binding domains knowledge about RNA binding proteins and their role in tumorigenesis as well as the potential to target RBPs for Cancer therapeutics cancer therapeutics. Small molecules © 2019 Elsevier Inc. All rights reserved. siRNA Peptide Aptamer Contents 1. Introduction................................................ 1 2. RNA-bindingdomains........................................... 2 3. AberrantexpressionofRBPsincancer.................................... 4 4. RBPsastherapeutictargetsforcancer.................................... 9 5. Conclusionsandfutureperspectives.................................... 14 DeclarationsofCompetingInterest....................................... 14 Financialsupport............................................... 14 Acknowledgments.............................................. 14 References.................................................. 14 1. Introduction Reinberg, 2002). Once an mRNA is transcribed, it is subjected to various processing, mainly controlled by RNA-binding proteins (RBPs) (Keene, A majority of eukaryotic genes are regulated at transcriptional and 2007). RBPs coordinately bind to each mRNA and form ribonucleopro- post-transcriptional levels, giving each one a unique expression profile tein (RNP) complexes. The composition of the RNP complexes is dy- under specific conditions (K. Chen & Rajewsky, 2007; Orphanides & namic based on the specific RNA processing. Notably, although RBPs bind to various classes of RNAs such as ribosomal RNAs, mRNAs, Abbreviations: 3′UTR, 3′ untranslated region; 5′UTR, 5′ untranslated region; AML, snRNA, snoRNA, tRNAs, and non-coding RNAs, about half of the RBPs Acute myeloid leukemia; ARE, AU-rich element; ASO, Antisense oligonucleotide; manifest their function by binding to mRNAs and exert their distinct circRNAs, Circular RNAs; CML, Chronic myeloid leukemia; dsRBD, Double-stranded RNA roles in regulating mRNA fate (J. Zhang & Chen, 2008). Given the impor- binding domain; dsRNA, Double-stranded RNA; hnRNP, heterogeneous nuclear ribonu- cleoprotein; KH, K-homology; miRNAs, MicroRNAs; mRNAs, Messenger RNAs; PAZ, tant role of RBPs in various cellular processes, such as transcription, Piwi/Argonaute/Zwille; PCBP, poly(C)-binding protein; PIWI, P-element Induced WImpy splicing, mRNA stability, mRNA transport and translation, it comes as testis; PUM, Pumilio homology domain; RBD, RNA-binding domain; RBP, RNA-binding no surprise that alterations in RBP expression or RBP mutations can protein; RNP, Ribonucleoprotein; RRM, RNA recognition motif; siRNA, Small interfering lead to various diseases, including cancer (Kechavarzi & Janga, 2014; RNA; TTP, Tristetraprolin; UTR, Untranslated region; ZNF, Zinc finger. Neelamraju, Gonzalez-Perez, Bhat-Nakshatri, Nakshatri, & Janga, 2018; ⁎ Corresponding author at: University of California at Davis, 2128A Tupper Hall, Davis, CA 95616, United States. Pereira, Billaud, & Almeida, 2017). Indeed, recent studies have found E-mail address: [email protected] (J. Zhang). that altered expression, localization or post-translational modification https://doi.org/10.1016/j.pharmthera.2019.07.001 0163-7258/© 2019 Elsevier Inc. All rights reserved. 2 S. Mohibi et al. / Pharmacology & Therapeutics 203 (2019) 107390 of RBPs can contribute to tumorigenesis by not only increasing expres- Y)-V-X-(F/Y), whereas RNP2 contains 6 amino acids with the consensus sion of oncogenes but also decreasing the expression of tumor suppres- sequence, (L/I)-(F/Y)-(V/I)-X-(N/G)-L. Structurally, the RRM domain is sor genes. Thus, increasing attention has been paid to the roles of RBPs composed of four anti-parallel β sheets stacked against two α helices, in cancer as well as the potential of targeting RBPs for cancer therapeu- giving it the β1α1β2β3α2β4 topology with RNP1 and RNP2 motifs mak- tics. In this review, we will discuss various functional domains of RBPs ing the central β3andβ1 sheets, respectively. Most of the RRMs contain and the role of RBPs in malignant transformation. We will also discuss three conserved aromatic amino acids in the central β strands, which recent advances and new insights into targeting RBPs for cancer allow for the recognition of two nucleotides. Some RRMs lack one or therapeutics. more of the conserved aromatic residues forming the derivative RRM domains such as the quasi-RRM, the pseudo-RRM or U2AF homology 2. RNA-binding domains motifs. Additional nucleotides can be recognized by the RRM using other aromatic and planar side-chains present on other β strands. In RBPs were initially identified due to their capability to bind various general, each RRM domain can recognize anywhere between 4 and 8 types of RNAs through an RNA-binding domain (RBD) that forms steady nucleotides by using β-sheet surface extensions or by using exposed secondary and tertiary structures. The classical RBDs include the K- loops connecting β-sheet to a β-sheet or α-helix. To achieve sequence homology domain (KH), RNA recognition motif (RRM), Zinc finger do- specificity and affinity for an mRNA, RBPs generally contain more than main (ZNF), Pumilio homology domain (PUM), double stranded RNA one RRM and bind RNA cooperatively. This has been demonstrated binding domain (dsRBD), and others (Fig. 1)(Lunde, Moore, & Varani, with the structures of several tandem RRMs bound to RNA, such as 2007). Due to the recently developed high-throughput approaches, HuD and nucleolin (Allain, Bouvet, Dieckmann, & Feigon, 2000;X. the number of RBPs has been largely increased to 1542 (Baltz et al., Wang & Tanaka Hall, 2001). In other cases, some RRMs do not coordi- 2012; Castello et al., 2012; Gerstberger, Hafner, & Tuschl, 2014; Wang nate with each other and appear to bind RNA independently. For exam- et al., 2018), comprising about ~7.5% of the protein coding genes. Inter- ple, the RRM1 and RRM2 in PTB are clearly independent from each other estingly, among them, only a quarter of RBPs contain classical RNA- and are separated by long flexible linkers (Oberstrass et al., 2005). The binding domains (RBDs) and the rest of them contain non-canonical different binding affinity among RRMs may be critical for target RBDs that have previously uncharacterized motifs (Baltz et al., 2012). selection. These non-canonical RBPs are unique in that they have intrinsically dis- ordered regions that adapt their structure upon contacting to RNAs and 2.2. hnRNP-K-Homology domain (KH domain) subsequently mediate cell cycle regulation, metabolism, and signal transduction. For this section, we focus on some of the classical RNA- The heterogeneous nuclear ribonucleoprotein (hnRNP) K-homology binding domains present in canonical RBPs. For the non-canonical (KH) domain is approximately 70 amino acids long and was initially RBPs, readers are referred to these recent reviews (Hentze, Castello, identified in the human hnRNP-K protein more than two decades ago Schwarzl, & Preiss, 2018; Moore, Jarvelin, Davis, Bond, & Castello, 2018). (Siomi, Matunis, Michael, & Dreyfuss, 1993). There are two types of KH domains: the eukaryotic type I and prokaryotic type II, both of 2.1. RNA recognition motif (RRM) which comprise of three α-helices and a three-stranded anti-parallel β-sheets (Grishin, 2001; Valverde, Edwards, & Regan, 2008). While RNA-recognition motif (RRM), also called as ribonucleoprotein both type I and type II share a minimal βααβ core, they fold differently (RNP) domain, is one of the most abundant and classical RNA-binding due to the location of additional α and β elements. In the type I KH do- domain present in a number of RBPs (Maris, Dominguez, & Allain, main, the α and β elements are located at the C-terminus, whereas in 2005). Their abundance and early discovery also make them the most the type II KH domain, these elements are located at the N-terminus. studied RBD with N30 solved crystal structures of RRMs bound to their Additionally, KH domain contains a conserved “GXXG” loop motif and target RNA sequences. (Sickmier et al., 2006;X.Wang & Tanaka Hall, a variable loop. KH domain interacts with nucleotides through hydro- 2001). Each RRM is made up of about 90 amino acids and consists of gen bonds, electrostatic interactions, and shape complementarity. Gen- two conserved sub-motifs referred to as RNP1 and RNP2. RNP1 consists erally, each KH domain can recognize four nucleotides through a of 8 amino acids with the consensus sequence, (R/K)-G-(F/Y)-(G/A)-(F/ binding cleft formed by the α1 and α2 helices linked by the “GXXG” Fig. 1. Schematic representation of RNA-binding proteins (RBPs) with various RNA-binding domains (RBDs). Each RBD is drawn as colored boxes and their lengths
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