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Poly(A) RNA‐binding proteins and polyadenosine RNA: new members and novel functions

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Poly(A) RNA‐binding proteins (Pabs) bind with high affinity and specificity to polyadenosine RNA. Textbook models show a nuclear Pab, PABPN1, and a cytoplasmic Pab, PABPC, where the nuclear PABPN1 modulates poly(A) tail length and the cytoplasmic PABPC stabilizes poly(A) RNA in the cytoplasm and also enhances translation. While these conventional roles are critically important, the Pab family has expanded recently both in number and in function. A number of novel roles have emerged for both PAPBPN1 and PABPC that contribute to the fine‐tuning of gene expression. Furthermore, as the characterization of the nucleic acid binding properties of RNA‐binding proteins advances, additional proteins that show high affinity and specificity for polyadenosine RNA are being discovered. With this expansion of the Pab family comes a concomitant increase in the potential for Pabs to modulate gene expression. Further complication comes from an expansion of the potential binding sites for Pab proteins as revealed by an analysis of templated polyadenosine stretches present within the transcriptome. Thus, Pabs could influence mRNA fate and function not only by binding to the nontemplated poly(A) tail but also to internal stretches of adenosine. Understanding the diverse functions of Pab proteins is not only critical to understand how gene expression is regulated but also to understand the molecular basis for tissue‐specific diseases that occur when Pab proteins are altered. Here we describe both conventional and recently emerged functions for PABPN1 and PABPC and then introduce and discuss three new Pab family members, ZC3H14, hnRNP‐Q1, and LARP4. WIREs RNA 2014, 5:601–622. doi: 10.1002/wrna.1233 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications RNA Processing > 3' End Processing

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Pab protein domain structures and family members. The domain structures for the five Pab family members discussed in this review (PABPN1, PABPC, ZC3H14, hnRNP‐Q1, and LARP4) are schematized here. RNA binding modules are highlighted in colors that correspond with each of these proteins in subsequent figures. PABPN1 is a nuclear Pab that contains a stretch of 10 alanines (Ala10) that are expanded in OPMD, a glutamic acid‐rich domain (E‐rich), a coiled‐coil domain (CCD), an RNA recognition motif (RRM) that is responsible for high affinity polyadenosine RNA binding, as well as an arginine‐rich (R‐rich) domain at the C‐terminus. PABPC is a cytoplasmic Pab that interacts with polyadenosine RNA via RRMs 1‐4 and contains a C‐terminal Helical domain. ZC3H14 is a novel nuclear Pab that interacts with polyadenosine RNA via tandem CysCysCysHis (CCCH) zinc fingers and also contains an N‐terminal Proline Tryptophan Isoleucine‐like (PWI‐like) fold that mediates interactions with the nuclear pore, a glutamine‐rich (Q‐rich) domain of unknown function, and two putative classical nuclear localization signals (cNLSs). hnRNP‐Q1 is a novel cytoplasmic Pab that is presumed to bind polyadenosine RNA via RRMs (RRM1‐3) and contains an acidic N‐terminal domain as well as an Arginine Glycine Glycine (RGG) domain, both of which mediate protein–protein interactions. A putative weak cNLS is also present in hnRNP‐Q1. LARP4 is a novel cytoplasmic Pab that interacts with polyadenosine RNA via a La Motif (LaM) in conjunction with an RRM‐like 4 domain (RRM‐L4). LARP4 interacts with PABPC via a poly(A) binding protein interacting motif (PAM2) domain that contains an atypical tryptophan in the consensus sequence (PAM2w).
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Prevalence and location of templated, internal polyadenosine stretches within the human transcriptome. (a) Analysis of the human transcriptome for the frequency and enrichment of internal polyadenosine stretches containing at least 12 consecutive adenosines reveals that the vast majority (136,655 out of 139,334) of these sequences are located in the introns of mRNAs, whereas a much smaller fraction are located in exonic regions (2464 of 139,334), which includes 5′ and 3′UTR regions. A much smaller number of these internal adenosine stretches are found in sequences that can be either introns or exons as a result of alternative splice variants. (b) Internal polyadenosine stretches found in exonic sequences are almost exclusively located in untranslated regions. Further analysis of the ≥12 nt polyadenosine sequences that occur in mature mRNA transcripts reveals that almost all (99.9%) of these instances are located in the UTRs, with an extremely large percentage present in the 3′UTRs (96.9%) of mRNA transcripts. (c) Noncoding RNAs also include templated stretches of polyadenosine. A number (428) of noncoding RNAs (yellow circle) contain templated polyadenosine sequences, suggesting that Pabs could modulate non‐coding RNAs through this templated binding site. Consistent with a model of 3′UTR regulation, a large number of the internal polyadenosine stretches identified in ncRNAs (138) are transcribed from regions that correspond to the 3′UTRs of other/host genes (yellow and green overlap).
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Model for the function of novel Pab family members. The functions proposed for the new members of the Pab family described here (ZC3H14, hnRNP‐Q1, and LARP4) are illustrated. The novel nuclear zinc finger Pab, ZC3H14 (pink five‐fingered shape) plays a role in 1. poly(A) tail length regulation: ZC3H14 could limit poly(A) tail length either by inhibiting Poly(A) Polymerase (PAP) or by recruiting a 3′→5′ exonuclease (gray Pac‐man); 2. Autoregulation: Like its Saccharomyces cerevisiae counterpart, Nab2, ZC3H14 may bind to and autoregulate its own mRNA transcript via an A15 stretch present in the 3′UTR; and 3. Generation of export‐competent mRNPs: ZC3H14 could play a direct role in the generation of properly packaged mRNPs that are poised for export but most data to support this function comes from studies of S. cerevisiae Nab2. Alternatively, proper polyadenylation could be required to assemble export‐competent mRNPs and the role for Nab2/ZC3H14 could be indirect. The novel cytoplasmic Pab, hnRNP‐Q1 (yellow ellipse), plays a role in 4. Translation inhibition: hnRNP‐Q1 competes with PABPC for binding to poly(A) tails and consequently prevents the formation of the translation initiation complex. The other novel cytoplasmic Pab, LARP4 (purple rectangle), is implicated in 5. Translation enhancement and increased mRNA stability: LARP4 interacts with PABPC as well as the ribosome‐associated protein, RACK1, to positively modulate mRNA translation and decay. The following factors are also incorporated into the model shown: Cap‐binding proteins 20 and 80 (CBP20/80); 7 methylguanosine cap (m7G); eukaryotic translation initiation factor 4E (eIF4E); eukaryotic translation initiation factor 4G (eIF4G); and eukaryotic ribosome (80S).
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Model for novel functions of PABPN1 and PABPC. (a) Recent studies reveal that PABPN1 (green hexagon) plays diverse roles in modulating gene expression that extend beyond those shown in Figure including impacting: 1. Alternative polyadenylation site selection: Loss‐of‐PABPN1 function leads to preferential use of PASs, which are often weak sites relative to the commonly used distal sites; 2. Nuclear mRNA decay pathway: PABPN1 coordinates with other RNA processing factors (not shown) to generate hyperadenylated mRNAs (indicated by red As) that target the transcript for degradation via a novel nuclear mRNA decay pathway; 3. Regulation of lncRNA: PABPN1 also promotes the turnover, via the RNA exosome (Exo), of a specific subset of long noncoding RNAs (lncRNAs) in an oligoadenylation‐dependent manner; and 4. Pioneer round of translation: PABPN1 remains bound to mRNAs as they exit the nucleus and enter the pioneer round of translation. PABPN1 likely cooperates with the exon junction complex (EJC) and PABPC and is replaced by PABPC following the pioneer round of translation. (b) Recent work reveals that PABPC (blue circle) is required for a number of functions beyond control of translation and regulation of mRNA decay illustrated in Figure . These functions include: 5. L1 mRNP nuclear import: Although the mechanism is unknown, PABPC is required for the nuclear accumulation of the LINE1 Ribonucleoprotein (L1 RNP); 6. mRNA translation, localization, and local translation: PABPC can modulate the translation and may modulate the localization and local translation of specific mRNA transcripts by binding to internal A‐rich sequences; 7. miRNA‐mediated translational repression, deadenylation, and decay: PABPC promotes RNA‐induced silencing complex (RISC) recruitment by binding to the RISC protein, GW182, which leads to the removal of PABPC, disruption of the closed loop structure and deadenylation by recruited deadenylase complexes; and 8. Nonsense mediated decay: PABPC inhibits recruitment of the nonsense mediated decay protein, Upf1, by interacting with eukaryotic release factor 3 (eRF3). The following factors are also incorporated into the model shown: Cap‐binding proteins 20 and 80 (CBP20/80); 7 methylguanosine cap (m7G); cleavage and polyadenylation specificity factor (CPSF); Poly(A) polymerase (PAP); eukaryotic translation initiation factor 4E (eIF4E); eukaryotic small ribosome (40S); eukaryotic translation initiation factor 4A (eIF4A); eukaryotic ribosome (80S); and eukaryotic release factor 1 (eRF1).
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Model for the canonical functions of PABPN1 and PABPC. The role of PABPN1 (green hexagon) in modulating 3′ end processing of mRNA transcripts is well established and consists of the following molecular functions: 1. Polyadenylation: PABPN1 interacts with poly(A) polymerase to stimulate processive polyadenylation; 2. Regulation of poly(A) tail length: PABPN1 interacts with the cleavage and polyadenylation specificity factor (CPSF) to modulate and ensure proper poly(A) tail length; and 3. Poly(A) RNA export: Although whether the role is direct or indirect is unknown, defects in PABPN1 function can lead to nuclear accumulation of poly(A) RNA. This observation together with the fact that PABPN1 shuttles between the nucleus and the cytoplasm have led to the suggestion that PABPN1 function is required for efficient poly(A) RNA export from the nucleus. PABPC (blue circle) plays a well‐defined role in modulating gene expression including: 4. Translation: PABPC binds to eukaryotic translation initiation factor 4G (eIF4G), which bridges interactions between the 5′‐ and 3′‐ends of the mRNA and facilitates efficient translation initiation and 5. mRNA decay: PABPC facilitates ribosome recycling by binding to eukaryotic release factor 3 (eRF3) and inhibits mRNA decay by protecting the mRNA from decapping enzymes (Dcp1 and Dcp2) and exonucleases, such as the Ccr4‐Pop2‐Not complex. The following factors are also incorporated into the model shown: Cap‐binding proteins 20 and 80 (CBP20/80); 7 methylguanosine cap (m7G); eukaryotic translation initiation factor 4E (eIF4E); eukaryotic small ribosome (40S); eukaryotic translation initiation factor 4A (eIF4A); eukaryotic ribosome (80S); and eukaryotic release factor 1 (eRF1).
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RNA Processing > 3′ End Processing
RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications

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