Family Of RNA-binding Proteins Research Articles

Structural basis of 3'-end poly(A) RNA recognition by LARP1.

La-related proteins (LARPs) comprise a family of RNA-binding proteins involved in a wide range of posttranscriptional regulatory activities. LARPs share a unique tandem of two RNA-binding domains, La motif (LaM) and RNA recognition motif (RRM), together referred to as a La-module, but vary in member-specific regions. Prior structural studies of La-modules reveal they are pliable platforms for RNA recognition in diverse contexts. Here, we characterize the La-module of LARP1, which plays an important role in regulating synthesis of ribosomal proteins in response to mTOR signaling and mRNA stabilization. LARP1 has been well characterized functionally but no structural information exists for its La-module. We show that unlike other LARPs, the La-module in LARP1 does not contain an RRM domain. The LaM alone is sufficient for binding poly(A) RNA with submicromolar affinity and specificity. Multiple high-resolution crystal structures of the LARP1 LaM domain in complex with poly(A) show that it is highly specific for the RNA 3′-end, and identify LaM residues Q333, Y336 and F348 as the most critical for binding. Use of a quantitative mRNA stabilization assay and poly(A) tail-sequencing demonstrate functional relevance of LARP1 RNA binding in cells and provide novel insight into its poly(A) 3′ protection activity.

Theoretical studies on RNA recognition by Musashi 1 RNA-binding protein

The Musashi (MSI) family of RNA-binding proteins, comprising the two homologs Musashi-1 (MSI1) and Musashi-2 (MSI2), typically regulates translation and is involved in cell proliferation and tumorigenesis. MSI proteins contain two ribonucleoprotein-like RNA-binding domains, RBD1 and RBD2, that bind single-stranded RNA motifs with a central UAG trinucleotide with high affinity and specificity. The finding that MSI also promotes the replication of Zika virus, a neurotropic Flavivirus, has triggered further investigations of the biochemical principles behind MSI–RNA interactions. However, a detailed molecular understanding of the specificity of MSI RBD1/2 interaction with RNA is still missing. Here, we performed computational studies of MSI1–RNA association complexes, investigating different RNA pentamer motifs using molecular dynamics simulations with binding free energy calculations based on the solvated interaction energy method. Simulations with Alphafold2 suggest that predicted MSI protein structures are highly similar to experimentally determined structures. The binding free energies show that two out of four RNA pentamers exhibit a considerably higher binding affinity to MSI1 RBD1 and RBD2, respectively. The obtained structural information on MSI1 RBD1 and RBD2 will be useful for a detailed functional and mechanistic understanding of this type of RNA–protein interactions.

LIN28 Family in Testis: Control of Cell Renewal, Maturation, Fertility and Aging.

Male reproductive development starts early in the embryogenesis with somatic and germ cell differentiation in the testis. The LIN28 family of RNA-binding proteins promoting pluripotency has two members—LIN28A and LIN28B. Their function in the testis has been investigated but many questions about their exact role based on the expression patterns remain unclear. LIN28 expression is detected in the gonocytes and the migrating, mitotically active germ cells of the fetal testis. Postnatal expression of LIN28 A and B showed differential expression, with LIN28A expressed in the undifferentiated spermatogonia and LIN28B in the elongating spermatids and Leydig cells. LIN28 interferes with many signaling pathways, leading to cell proliferation, and it is involved in important testicular physiological processes, such as cell renewal, maturation, fertility, and aging. In addition, aberrant LIN28 expression is associated with testicular cancer and testicular disorders, such as hypogonadotropic hypogonadism and Klinefelter’s syndrome. This comprehensive review encompasses current knowledge of the function of LIN28 paralogs in testis and other tissues and cells because many studies suggest LIN28AB as a promising target for developing novel therapeutic agents.

Abstract 2564: CDK9 inhibition via KB-0742 is a potential strategy to treat transcriptionally addicted cancers

Abstract Lineage-specific transcriptional networks drive cellular differentiation and development. Disruption of these specific cell programs can result in cancer and create a subset of tumors that are “transcriptionally addicted.” Sarcomas, for example, are characterized by an oncogenic fusion protein consisting of a FET family RNA-binding protein fused to a transcription factor (TF). The oncogenic fusions result in a restructuring of the transcriptome promoting cancer. In chordoma, TBXT (brachyury)—normally involved in notochord differentiation—is aberrantly expressed, resulting in promotion of cancer. As these oncogenic TFs are difficult to target directly, we and others have proposed targeting associated transcriptional regulators to inhibit their activity. Cyclin-dependent kinase 9 (CDK9) interacts with TFs to promote activation of target genes and promotes transcription elongation through phosphorylation of RNA polymerase II. We have developed a potent, selective, and orally bioavailable CDK9 inhibitor, KB-0742. Here we present the preclinical activity of KB-0742 in models of sarcoma and chordoma. We first evaluated KB-0742 activity in sarcoma in a 300-immortalized cell line screen containing 18 soft tissue sarcoma cell lines. The median IC50 of the cell lines in the study was 0.8705 µM. Sarcoma cell lines were enriched for sensitivity to KB-0742 with 61% (11/18) of the lines with an IC50 below the median. The 11 cell lines had a median IC50 of 0.679 µM. We then evaluated the activity of KB-0742 in 5 patient-derived cell line (PDC) models, with all 5 showing a cytotoxic response to treatment as measured by negative GRmax values. Last, a single patient-derived organoid (PDO) model of adult rhabdomyosarcoma was evaluated. KB-0742 treatment resulted in an IC50 of 2.75 µM and a max inhibition rate of 98.61%. For chordoma we examined the activity of KB-0742 in vivo using 2 patient-derived xenograft (PDX) models. In model CF466, we observed a dose-dependent response with increased TGI and greater reductions in RNA polymerase II phosphorylation in tumors treated with KB-0742 at 60 mg/kg as compared to 30 mg/kg. We then evaluated KB-0742 as a single agent and in combination with afatinib in the model CF539. KB-0742 as a single agent showed similar TGI activity as afatinib, whereas the combination showed increased response as compared to the two single-agent arms. These data show that transcriptionally addicted tumors are sensitive to CDK9 inhibition via KB-0742 treatment, and support the continued development of our compound to potentially treat sarcoma and chordoma. KB-0742 is currently being evaluated in a phase 1/2 clinical trial (NCT04718675) for relapsed or refractory solid tumors or non-Hodgkin lymphoma. Once a recommended phase 2 dose is established, expansion cohorts for patients with sarcoma, chordoma, and other transcriptionally addicted tumors may be opened. Citation Format: Melinda A. Day, Douglas C. Saffran, Tressa Hood, Nikolaus Obholzer, Akanksha Pandey, Charles Y. Lin, Pavan Kumar, Daniel M. Freed, Jorge DiMartino. CDK9 inhibition via KB-0742 is a potential strategy to treat transcriptionally addicted cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2564.

The Fragile X Protein Disordered Regions Bind a Novel RNA Target.

The fragile X proteins (FXPs) are a family of RNA-binding proteins that regulate mRNA translation to promote proper neural development and cognition in mammals. Of particular interest to researchers is the fragile X mental retardation protein (FMRP), as its absence leads to a neurodevelopmental disorder: fragile X syndrome (FXS), the leading monogenetic cause of autism spectrum disorders. A primary focus of research has been to determine mRNA targets of the FXPs in vivo through pull-down techniques, and to validate them through in vitro binding studies; another approach has been to perform in vitro selection experiments to identify RNA sequence and structural targets. These mRNA targets can be further investigated as potential targets for FXS therapeutics. The most established RNA structural target of this family of proteins is the G-quadruplex. In this article, we report a 99 nucleotide RNA target that is bound by all three FXPs with nanomolar equilibrium constants. Furthermore, we determined that the last 102 amino acids of FMRP, which includes the RGG motif, were necessary and sufficient to bind this RNA target. To the best of our knowledge, this is one of only a few examples of non-G-quadruplex, non-homopolymer RNAs bound by the RGG motif/C-termini of FMRP.

Species-specific formation of paraspeckles in intestinal epithelium revealed by characterization of NEAT1 in naked mole-rat.

Paraspeckles are mammalian-specific nuclear bodies built on the long noncoding RNA NEAT1_2 The molecular mechanisms of paraspeckle formation have been mainly studied using human or mouse cells, and it is not known if the same molecular components are involved in the formation of paraspeckles in other mammalian species. We thus investigated the expression pattern of NEAT1_2 in naked mole-rats (nNEAT1_2), which exhibit extreme longevity and lower susceptibility to cancer. In the intestine, nNEAT1_2 is widely expressed along the entire intestinal epithelium, which is different from the expression of mNeat1_2 that is restricted to the cells of the distal tip in mice. Notably, the expression of FUS, a FET family RNA binding protein, essential for the formation of paraspeckles both in humans and mice, was absent in the distal part of the intestinal epithelium in naked mole-rats. Instead, mRNAs of other FET family proteins EWSR1 and TAF15 were expressed in the distal region. Exogenous expression of these proteins in Fus-deficient murine embryonic fibroblast cells rescued the formation of paraspeckles. These observations suggest that nNEAT1_2 recruits a different set of RNA binding proteins in a cell type-specific manner during the formation of paraspeckles in different organisms.

Hu Antigen R (HuR) Protein Structure, Function and Regulation in Hepatobiliary Tumors.

Simple SummaryHepatobiliary tumors are a group of primary malignancies encompassing the liver, the intra- and extra-hepatic biliary tracts, and the gall bladder. Within the liver, hepatocellular carcinoma (HCC) is the most common type of primary cancer, which is, also, representing the third-most recurrent cause of cancer-associated death and the sixth-most prevalent type of tumor worldwide, nowadays. Although less frequent, cholangiocarcinoma (CCA) is, currently, a fatal cancer with limited therapeutic options. Here, we review the regulatory role of Hu antigen R (HuR), a ubiquitous member of the ELAV/Hu family of RNA-binding proteins (RBPs), in the pathogenesis, progression, and treatment of HCC and CCA. Overall, HuR is proposed as a valuable diagnostic and prognostic marker, as well as a therapeutic target in hepatobiliary cancers. Therefore, novel therapeutic approaches that can selectively modulate HuR function appear to be highly attractive for the clinical management of these types of tumors.Hu antigen R (HuR) is a 36-kDa ubiquitous member of the ELAV/Hu family of RNA-binding proteins (RBPs), which plays an important role as a post-transcriptional regulator of specific RNAs under physiological and pathological conditions, including cancer. Herein, we review HuR protein structure, function, and its regulation, as well as its implications in the pathogenesis, progression, and treatment of hepatobiliary cancers. In particular, we focus on hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), tumors where the increased cytoplasmic localization of HuR and activity are proposed, as valuable diagnostic and prognostic markers. An overview of the main regulatory axes involving HuR, which are associated with cell proliferation, invasion, metastasis, apoptosis, and autophagy in HCC, is provided. These include the transcriptional, post-transcriptional, and post-translational modulators of HuR function, in addition to HuR target transcripts. Finally, whereas studies addressing the relevance of targeting HuR in CCA are limited, in the past few years, HuR has emerged as a potential therapeutic target in HCC. In fact, the therapeutic efficacy of some pharmacological inhibitors of HuR has been evaluated, in early experimental models of HCC. We, further, discuss the major findings and future perspectives of therapeutic approaches that specifically block HuR interactions, either with post-translational modifiers or cognate transcripts in hepatobiliary cancers.

The ZFP36 family of RNA-binding proteins regulate homeostatic and autoreactive T cell responses

Abstract The zinc finger 36 (ZFP36) family of RNA-binding proteins, consisting of ZFP36, ZFP36L1, and ZFP36L2, is known to negatively regulate mRNA stability and/or inhibit translation of many transcripts, including cytokines. While there are reports of all three family members regulating T cell cytokine production, delineating the functions of these genes is challenging due to spontaneous phenotypes upon global deletion of single genes and potential redundancy in their functions. To overcome this, we generated Cd4-Cre+ Zfp36fl/fl Zfp36l1fl/fl Zfp36l2fl/fl mice. Only upon triple deletion, but not individual or paired deletions, do mice spontaneously develop an inflammatory disease characterized by early lethality, hypercytokinemia, and immune cell infiltration into some peripheral organs, including the central nervous system. As SNPs in human ZFP36L1 and ZFP36L2 have been linked to susceptibility for multiple sclerosis, we tested ZFP36 family member individual and paired T cell-deficient mice in experimental autoimmune encephalomyelitis (EAE). To our surprise, Cd4-Cre+ Zfp36l1fl/fl Zfp36l2fl/fl mice were markedly protected from EAE clinical disease, while no change in disease severity was seen with any deletion strains involving Zfp36. There was a severe impairment in generating antigen-specific CD4+ T cells in Cd4-Cre+ Zfp36l1fl/fl Zfp36l2fl/fl mice during EAE priming. Our findings demonstrate a novel redundancy of the ZFP family members in regulating T cell homeostasis and a shared role for ZFP36L1 and ZFP36L2 to promote clonal expansion. Understanding the individual and shared functions of the ZFP36 family members may lead to opportunities to target them to suppress T cell-driven autoimmunity. M.E.C. supported by the National Science Foundation Graduate Research Fellowship program (DGE-1745038) and by grant 5T32AI007163 from the NIAID. B.T.E. supported by the NIAID (R01 AI113118).

The X-linked splicing regulator MBNL3 has been co-opted to restrict placental growth in eutherians

Understanding the regulatory interactions that control gene expression during the development of novel tissues is a key goal of evolutionary developmental biology. Here, we show that Mbnl3 has undergone a striking process of evolutionary specialization in eutherian mammals resulting in the emergence of a novel placental function for the gene. Mbnl3 belongs to a family of RNA-binding proteins whose members regulate multiple aspects of RNA metabolism. We find that, in eutherians, while both Mbnl3 and its paralog Mbnl2 are strongly expressed in placenta, Mbnl3 expression has been lost from nonplacental tissues in association with the evolution of a novel promoter. Moreover, Mbnl3 has undergone accelerated protein sequence evolution leading to changes in its RNA-binding specificities and cellular localization. While Mbnl2 and Mbnl3 share partially redundant roles in regulating alternative splicing, polyadenylation site usage and, in turn, placenta maturation, Mbnl3 has also acquired novel biological functions. Specifically, Mbnl3 knockout (M3KO) alone results in increased placental growth associated with higher Myc expression. Furthermore, Mbnl3 loss increases fetal resource allocation during limiting conditions, suggesting that location of Mbnl3 on the X chromosome has led to its role in limiting placental growth, favoring the maternal side of the parental genetic conflict.

RNA-binding protein hnRNP UL1 binds κB sites to attenuate NF-κB-mediated inflammation

Heterogeneous nuclear ribonucleoproteins (hnRNPs), a family of RNA-binding proteins, play important roles in various biological processes. However, the roles of hnRNPs members in immunity and inflammation remain to be fully understood. By a functional screening for hnRNPs members in LPS-stimulated macrophage inflammatory response, we identified hnRNP UL1 as a negative regulator of NF-κB-mediated inflammation. hnRNP UL1 constrains NF-κB-triggered transcriptional expression of pro-inflammatory cytokines in response to innate stimuli. Perturbation of hnRNP UL1 enhanced pro-inflammatory cytokine production in macrophages. In vivo deficiency of hnRNP UL1 increased the pro-inflammatory cytokine production once challenged with LPS. Accordingly, the expression of hnRNP UL1 decreased in peripheral blood mononuclear cells of rheumatoid arthritis patients. Mechanistically, hnRNP UL1 competes with NF-κB to bind κB sites to constrain the magnitude and duration of inflammatory response. Meanwhile, the broadly and dynamically binding of hnRNP UL1 on the target genes’ promoter during inflammatory response is unraveled. Our study adds new insight into the functions of hnRNPs in NF-κB-mediated inflammation, proposing a potential therapeutic strategy for controlling inflammatory autoimmune diseases.

Backbone and sidechain 1H, 15N and 13C resonance assignments of the free and RNA-bound tandem zinc finger domain of the tristetraprolin family member from Selaginella moellendorffii.

Members of the tristetraprolin (TTP) family of RNA binding proteins (RBPs) regulate the metabolism of a variety of mRNA targets. In mammals, these proteins modulate many physiological processes, including immune cell activation, hematopoiesis, and embryonic development. Regulation of mRNA stability by these proteins requires that the tandem zinc finger (TZF) domain binds initially and directly to target mRNAs, ultimately leading to their deadenylation and decay. Proteins of this type throughout eukarya possess a highly conserved TZF domain, suggesting that they are all capable of high-affinity RNA binding. However, the mechanism of TTP-mediated mRNA decay is largely undefined. Given the vital role that these TTP family proteins play in maintaining RNA homeostasis throughout eukaryotes, we focused here on the first, key step in this process: recognition and binding of the TZF domain to target RNA. For these studies, we chose a primitive plant, the spikemoss Selaginella moellendorffii, which last shared a common ancestor with humans more than a billion years ago. Here we report the near complete backbone and side chain resonance assignments of the spikemoss TZF domain, including: (1) the assignment of the RNA-TZF domain complex, representing one of only two data sets currently available for the entire TTP family of proteins; and (2) the first NMR resonance assignments of the entire TZF domain, in the RNA-free form. This work will serve as the basis for further NMR structural investigations aimed at gaining insights into the process of RNA recognition and the mechanisms of TTP-mediated mRNA decay.

Regulation of the Alternative Neural Transcriptome by ELAV/Hu RNA Binding Proteins.

The process of alternative polyadenylation (APA) generates multiple 3' UTR isoforms for a given locus, which can alter regulatory capacity and on occasion change coding potential. APA was initially characterized for a few genes, but in the past decade, has been found to be the rule for metazoan genes. While numerous differences in APA profiles have been catalogued across genetic conditions, perturbations, and diseases, our knowledge of APA mechanisms and biology is far from complete. In this review, we highlight recent findings regarding the role of the conserved ELAV/Hu family of RNA binding proteins (RBPs) in generating the broad landscape of lengthened 3' UTRs that is characteristic of neurons. We relate this to their established roles in alternative splicing, and summarize ongoing directions that will further elucidate the molecular strategies for neural APA, the in vivo functions of ELAV/Hu RBPs, and the phenotypic consequences of these regulatory paradigms in neurons.

The 1H, 15N and 13C resonance assignments of the low-complexity domain from the oncogenic fusion protein EWS-FLI1.

The RNA-binding protein EWS is a multifunctional protein with roles in the regulation of transcription and RNA splicing. It is one of the FET (FUS, EWS and TAF15) family of RNA binding proteins that contain an intrinsically disordered, low-complexity N-terminal domain. The FET family proteins are prone to chromosomal translocations, often fusing their low-complexity domain with a transcription factor derived DNA-binding domain, that are oncogenic drivers in several leukemias and sarcomas. The fusion protein disrupts the normal function of cells through non-canonical DNA binding and alteration of normal transcriptional programs. However, the exact mechanism for how the intrinsically disordered domain contributes to aberrant DNA binding and abnormal transcription is unknown. The purification and 1H, 13C, and 15N backbone resonance assignments of the amino terminal domain comprising 264 residues of EWS is described. This segment is common to all known EWS-fusions that are the hallmark of the pediatric cancer Ewing sarcoma. This domain is intrinsically disordered and features significant sequence degeneracy resulting in spectra with poor chemical shift dispersion. To alleviate this problem, the domain was divided into three overlapping fragments, reducing the complexity of the spectra and enabling almost complete backbone resonance assignment of the full domain. These solution NMR chemical shift assignments represent the first steps towards understanding, at atomic resolution, how the low-complexity domain of EWS contributes to the aberrant functions of its oncogenic fusion proteins.

Rbfox1 is required for myofibril development and maintaining fiber type-specific isoform expression in Drosophila muscles.

Protein isoform transitions confer muscle fibers with distinct properties and are regulated by differential transcription and alternative splicing. RNA-binding Fox protein 1 (Rbfox1) can affect both transcript levels and splicing, and is known to contribute to normal muscle development and physiology in vertebrates, although the detailed mechanisms remain obscure. In this study, we report that Rbfox1 contributes to the generation of adult muscle diversity in Drosophila Rbfox1 is differentially expressed among muscle fiber types, and RNAi knockdown causes a hypercontraction phenotype that leads to behavioral and eclosion defects. Misregulation of fiber type-specific gene and splice isoform expression, notably loss of an indirect flight muscle-specific isoform of Troponin-I that is critical for regulating myosin activity, leads to structural defects. We further show that Rbfox1 directly binds the 3'-UTR of target transcripts, regulates the expression level of myogenic transcription factors myocyte enhancer factor 2 and Salm, and both modulates expression of and genetically interacts with the CELF family RNA-binding protein Bruno1 (Bru1). Rbfox1 and Bru1 co-regulate fiber type-specific alternative splicing of structural genes, indicating that regulatory interactions between FOX and CELF family RNA-binding proteins are conserved in fly muscle. Rbfox1 thus affects muscle development by regulating fiber type-specific splicing and expression dynamics of identity genes and structural proteins.

The disease-associated proteins Drosophila Nab2 and Ataxin-2 interact with shared RNAs and coregulate neuronal morphology.

Nab2 encodes the Drosophila melanogaster member of a conserved family of zinc finger polyadenosine RNA-binding proteins (RBPs) linked to multiple steps in post-transcriptional regulation. Mutation of the Nab2 human ortholog ZC3H14 gives rise to an autosomal recessive intellectual disability but understanding of Nab2/ZC3H14 function in metazoan nervous systems is limited, in part because no comprehensive identification of metazoan Nab2/ZC3H14-associated RNA transcripts has yet been conducted. Moreover, many Nab2/ZC3H14 functional protein partnerships remain unidentified. Here, we present evidence that Nab2 genetically interacts with Ataxin-2 (Atx2), which encodes a neuronal translational regulator, and that these factors coordinately regulate neuronal morphology, circadian behavior, and adult viability. We then present the first high-throughput identifications of Nab2- and Atx2-associated RNAs in Drosophila brain neurons using RNA immunoprecipitation-sequencing (RIP-Seq). Critically, the RNA interactomes of each RBP overlap, and Nab2 exhibits high specificity in its RNA associations in neurons in vivo, associating with a small fraction of all polyadenylated RNAs. The identities of shared associated transcripts (e.g., drk, me31B, stai) and of transcripts specific to Nab2 or Atx2 (e.g., Arpc2 and tea) promise insight into neuronal functions of, and genetic interactions between, each RBP. Consistent with prior biochemical studies, Nab2-associated neuronal RNAs are overrepresented for internal A-rich motifs, suggesting these sequences may partially mediate Nab2 target selection. These data support a model where Nab2 functionally opposes Atx2 in neurons, demonstrate Nab2 shares associated neuronal RNAs with Atx2, and reveal Drosophila Nab2 associates with a more specific subset of polyadenylated mRNAs than its polyadenosine affinity alone may suggest.

RNA-binding motif protein 10 represses tumor progression through the Wnt/β- catenin pathway in lung adenocarcinoma.

RNA-binding motif protein 10 (RBM10), one of the members of the RNA-binding protein (RBP) family, has a tumor suppressor role in multiple cancers. However, the functional role of RBM10 in lung adenocarcinoma (LUAD) and the underlying molecular mechanism remains unclear. In this study, we observed that RBM10 is significantly downregulated in LUAD tissues compared with normal tissues. Low RBM10 expression is significantly associated with poor outcome of LUAD patients. In vitro and in vivo experiments show that RBM10 inhibits cell proliferation, metastasis and EMT progression in LUAD. Mechanistically, we demonstrate that RBM10 interacts with β-catenin interacting protein 1 (CTNNBIP1) and positively regulates its expression, disrupting the binding of β-catenin to the transcription factor TCF/LEF, thereby inactivating the Wnt/β-catenin pathway. In conclusion, this is the first study reporting the role of RBM10 in suppressing LUAD progression at least via partly inactivating the Wnt/β-catenin pathway, which provides new insights into the tumorigenesis and metastasis of LUAD. Thus, RBM10 may be a promising new therapeutic target or clinical biomarker for LUAD therapy in the future.

The Role of Pumilio RNA Binding Protein in Plants.

Eukaryotic organisms have a posttranscriptional/translational regulation system for the control of translational efficiency. RNA binding proteins (RBPs) have been known to control target genes. One type of protein, Pumilio (Pum)/Puf family RNA binding proteins, show a specific binding of 3′ untranslational region (3′ UTR) of target mRNA and function as a post-transcriptional/translational regulator in eukaryotic cells. Plant Pum protein is involved in development and biotic/abiotic stresses. Interestingly, Arabidopsis Pum can control target genes in a sequence-specific manner and rRNA processing in a sequence-nonspecific manner. As shown in in silico Pum gene expression analysis, Arabidopsis and rice Pum genes are responsive to biotic/abiotic stresses. Plant Pum can commonly contribute to host gene regulation at the post-transcriptional/translational step, as can mammalian Pum. However, the function of plant Pum proteins is not yet fully known. In this review, we briefly summarize the function of plant Pum in defense, development, and environmental responses via recent research and bioinformatics data.

Distinct roles of hnRNPH1 low-complexity domains in splicing and transcription

Heterogeneous nuclear ribonucleoproteins (hnRNPs) represent a large family of RNA-binding proteins that control key events in RNA biogenesis under both normal and diseased cellular conditions. The low-complexity (LC) domain of hnRNPs can become liquid-like droplets or reversible amyloid-like polymers by phase separation. Yet, whether phase separation of the LC domains contributes to physiological functions of hnRNPs remains unclear. hnRNPH1 contains two LC domains, LC1 and LC2. Here, we show that reversible phase separation of the LC1 domain is critical for both interaction with different kinds of RNA-binding proteins and control of the alternative-splicing activity of hnRNPH1. Interestingly, although not required for phase separation, the LC2 domain contributes to the robust transcriptional activation of hnRNPH1 when fused to the DNA-binding domain, as found recently in acute lymphoblastic leukemia. Our data suggest that the ability of the LC1 domain to phase-separate into reversible polymers or liquid-like droplets is essential for function of hnRNPH1 as an alternative RNA-splicing regulator, whereas the LC2 domain may contribute to the aberrant transcriptional activity responsible for cancer transformation.

The RNA-Binding Motif Protein Family in Cancer: Friend or Foe?

The RNA-binding motif (RBM) proteins are a class of RNA-binding proteins named, containing RNA-recognition motifs (RRMs), RNA-binding domains, and ribonucleoprotein motifs. RBM proteins are involved in RNA metabolism, including splicing, transport, translation, and stability. Many studies have found that aberrant expression and dysregulated function of RBM proteins family members are closely related to the occurrence and development of cancers. This review summarizes the role of RBM proteins family genes in cancers, including their roles in cancer occurrence and cell proliferation, migration, and apoptosis. It is essential to understand the mechanisms of these proteins in tumorigenesis and development, and to identify new therapeutic targets and prognostic markers.

Interconnected Gene Networks Underpin the Clinical Overlap of HNRNPH1-Related and Rubinstein-Taybi Intellectual Disability Syndromes.

Interconnected Gene Networks Underpin the Clinical Overlap of HNRNPH1-Related and Rubinstein-Taybi Intellectual Disability Syndromes.