Westermarck J., Weiss C., Saffrich R., Kast J., Musti A.M., Wessely M., Ansorge W., Seraphin B., Wilm M., Valdez B.C., et al. eCollection 2018. Pellizzoni L., Charroux B., Rappsilber J., Mann M., Dreyfuss G. A functional interaction between the survival motor neuron complex and RNA polymerase II. Their prominence is marked by various cancers and genetic disorders that are linked to helicase defects. Mol Endocrinol 10: 13351349. Lee M.B., Lebedeva L.A., Suzawa M., Wadekar S.A., Desclozeaux M., Ingraham H.A. Bookshelf RHA was also found to interact with the p65 subunit of NF-B and to enhance NF-B-dependent transcription (26), while the Drosophila homologue was shown to associate with, and stimulate the transcriptional activity of, a region upstream of the roX2 gene, which is critical for dosage compensation (27). In recent years, however, most of the reports on DP103 have concentrated on its role in transcription and have provided more direct evidence for its role as a transcriptional regulator. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Based on homology with the well-characterized DNA helicases (4) and the observation that some prototypic members exhibit RNA helicase activity in vitro, it has been proposed that DExD/H proteins act principally as ATP-dependent RNA helicases. Functional interaction between Smad, CREB binding protein, and p68 RNA helicase. Solid arrows indicate interactions documented in the literature; heavy dashed arrows are bridging roles suggested from the known interactions; faint dashed arrows with query marks are implied recruiting or bridging roles. p68 (Ddx5) is one of the prototypic members of the DEAD box family of proteins (47) and was one of the first proteins to be shown to exhibit RNA helicase activity in vitro (48). Thus RHA may possess a more general transcriptional activity through its association with CBP/RNA Pol II and also a more specific activity through its interaction with specific transcription factors and/or recruitment to specific promoters. 2021 May 19;16(5):e0251132. The idea that DExD/H proteins are acting as bridging factors to regulate transcription is particularly interesting when one considers that, in many cases, the interacting regions on the DExD/H proteins lie outside the conserved core, and could account for the high diversity and specificity of interactions exhibited by these proteins. A recent report has demonstrated that p68 acts as a potent coactivator for the tumour suppressor p53, a latent transcription factor that is induced and activated in response to stresses, such as DNA damage, and induces transcription of genes involved in cell cycle arrest and apoptosis. (96) recently for some coregulators of nuclear receptors, and by Bates et al. Direct interaction of SMN with DP103, a putative RNA helicase: a role for SMN in transcription regulation? This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. ChIP confirmed Hltf binding to consensus sequences in predicted (promoter Scgb3a1 gene) and previously unidentified (P-element on chromosome 7) targets. It is not yet clear whether the same applies for p72. 2008 Feb;65(4):591-604. doi: 10.1007/s00018-007-7392-4. Another very interesting idea that emerges from these findings is that DExD/H proteins may be acting to couple processes such as transcription and RNA processing. Time for remodeling: SNF2-family DNA translocases in replication fork metabolism and human disease. O'Gorman W., Kwek K.Y., Thomas B., Akoulitchev A. Non-coding RNA in transcription initiation. Ishizuka A., Siomi M.C., Siomi H. A Drosophila fragile X protein interacts with components of RNAi and ribosomal proteins. Concrete evidence that RHA (Dhx9) played an active role in transcription came from the findings of Nakajima et al. RHA has also been shown to interact with the promoters of the MDR1 and p16INK4A genes; therefore these are also indicated. In a subsequent study, Aratani et al. In this article I shall review current evidence demonstrating that some members of the DExD/H family have, in addition to their established roles as RNA helicases or unwindases, clear roles as transcriptional regulators which, in several cases, appear to be independent of their RNA helicase activity. In addition to the general functions of DNA helicases in DNA replication, DNA repair and recombination, chromosome segregation, and transcription initiation; a number of other processes that are controlled by DNA helicases have recently been discovered. transcription - RNA polymerase and DNA helicase - Biology Stack Exchange The DExD/H box family of proteins is distinguished by the presence of several conserved motifs, which include the characteristic DExD/H sequence (where x can be any amino acid) and are highly conserved in proteins from viruses and bacteria to humans (13). Auboeuf D., Dowhan D.H., Dutertre M., Martin N., Berget S.M., O'Malley B.W. AF1 functions in a ligand-independent manner while the activity of AF2 is regulated by estrogen binding, which results in a conformational change in this domain and thus facilitates coregulator recruitment. Regulation of alternative splicing by the ATP-dependent DEAD-box RNA helicase p72. National Library of Medicine This was reinforced by reports showing that p68 is overexpressed and abnormally modified in colorectal tumours (91), and that there are changes in p68 phosphorylation associated with transformation and abnormal cell proliferation (92). Federal government websites often end in .gov or .mil. The ATPase and/or helicase activity of RHA is required for CREB-dependent transcription. The helicase core is comprised of eight conserved motifs (motifs I, Ia, Ib, II, III, IV, V and VI). RNA helicase A (RHA) is a member of an ATPase/DNA and RNA helicase family and is a homologue of Drosophila maleless protein (MLE), which regulates X-linked gene expression. Taken together these different lines of evidence suggest that p68 may be important in cancer development. Therefore, the demonstration that several DExD/H proteins interact with proteins that are known to be involved in the transcriptional regulation of genes involved in DNA repair and cell growth/cell cycle control have highlighted potentially important roles for DExD/H proteins in the development of cancer. 2018 Jul 5;13(7):e0200211. Funding to pay the Open Access publication charges for this article was provided by Tenovus Scotland. Hence females have two active copies and males only . Models for mechanisms by which DExD/H box proteins, such as RHA and p68/p72, could recruit components of the transcription machinery to promoters or stabilize transcription initiation by acting as adaptor molecules or bridging factors, as suggested by the literature. PCR amplification of DNA fragments. Roles for DEAD (and DExH) box proteins in pre-mRNA and pre-rRNA processing have been well documented (2,62). Other examples of DExD/H proteins having possible implications for cell growth regulation, as a result of their function in transcriptional regulation, include DP103 and RHII/Gu. -, Zhang Q, Ekhterae D, Kim KH (1997) Molecular cloning and characterization of P113, a mouse SNF2/SWI2-related transcription factor. Wilson B.J., Bates G.J., Nicol S.M., Gregory D.J., Perkins N.D., Fuller-Pace F.V. Anderson S.F., Schlegel B.P., Nakajima T., Wolpin E.S., Parvin J.D. Hashimoto K., Nakagawa Y., Morikawa H., Niki M., Egashira Y., Hirata I., Katsu K., Akao Y. Co-overexpression of DEAD box protein rck/p54 and c-myc protein in human colorectal adenomas and the relevance of their expression in cultured cell lines. official website and that any information you provide is encrypted RNA polymerase is the main transcription enzyme. See also Figures S1 and S2. Hltf null brains have reduced transcript levels for Rad21/Scc1, histone H3.3, Cap-E/Smc2, Cap-G/G2, and Aurora B kinase. ll Cell 182, 1560-1573, September 17, 2020 1561 Article. This review focuses on the diverse functions of these proteins in the process of RNA polymerase II transcription in eukaryotes. The https:// ensures that you are connecting to the This work shows that the RTEL1 helicase has a crucial role in telomere maintenance by disassembling T-loops . 2, 5, 11, 12 Along with DNA helicases, RNA helicases can be grouped into 5 superfamilies (SF1-SF5) based on conservation of sequence motifs. Summary of the commonly used names and reported functions for RHA, DP103, p68 and p72. Here we uncovered the functions of RCF1 in Arabidopsis thaliana as a player in pri-miRNA processing and splicing, as well as in pre-mRNA splicing. Disclaimer. 13 Most RNA . Liu Z.R., Sargueil B., Smith C.W. p72: a human nuclear DEAD box protein highly related to p68. . Through its interaction with BRCA1, RHA may play an important role in the function of BRCA1 in the transcriptional regulation of genes involved in DNA repair/genome maintenance, cell cycle regulation and apoptosis (2325). Moreover, while overexpression of wild-type RHII/Gu had no effect on c-Jun-dependent transcription, overexpression of ATPase/helicase defective mutants or microinjection of anti-RHII/Gu antibody inhibited c-Jun transcription activity in vitro, suggesting that RHII/Gu is important for c-Jun transcription activation and that RHII/Gu helicase activity is involved in this function. The helicase-like transcription factor and its implication in cancer progression. Functions in nucleotide excision repair; component of BTF2TFIIH transcription factor. Panel B, higher magnification of the cholinergic-rich ventral paladium involved in regulation of motivation and behavior. eCollection 2013. Inclusion in an NLM database does not imply endorsement of, or agreement with, Human immunodeficiency virus type 1 (HIV-1) does not encode a helicase, thus it has to exploit cellular helicases in order to efficiently replicate its RNA genome. Historically, most DExD/H box proteins have been associated with such cellular processes; indeed many members of this family were initially identified through investigations of mutants that led to specific defects in processes such as RNA processing, ribosome biogenesis and translation, and it is clear that the RNA unwinding activity of these proteins is essential for their function in such processes (9). official website and that any information you provide is encrypted (17), who showed that RHA acts as a bridging factor between the CREB-binding protein (CBP) and RNA polymerase II (Pol II), thus cooperating with CBP to activate transcription. 8600 Rockville Pike Overexpression of a protein fragment of RNA helicase A causes inhibition of endogenous BRCA1 function and defects in ploidy and cytokinesis in mammary epithelial cells. Zhong X., Safa A.R. For many years it has been suggested that, while the conserved helicase core acts as a motor, the unique N- and C-terminal domains impart specificity to the interaction of these proteins with partner proteins, allowing them to unwind specific substrates. TFIIH: A multi-subunit complex at the cross-roads of transcription and Dual roles of RNA helicase A in CREB-dependent transcription However, mutants in both the transactivation domain and the ATP-binding motif exhibited reduced CREB-dependent transcriptional activity when co-transfected with plasmids encoding CBP and a CRE-luciferase reporter (19). For this purpose, I shall concentrate predominantly on those proteins for which most data are available in the literature: these include a member of the DExH subclass RNA helicase A (also known as Dhx9 and nuclear DNA helicase II), as well as the DEAD subclass proteins DP103 (also known as Ddx20 and Gemin3) and the highly related p68/p72 proteins (Ddx5/Ddx17). A schematic alignment of the human homologues of the DExD/H box proteins considered in this review, highlighting the different lengths of the divergent N- and C-terminal domains. Interestingly the association of Mle with the X chromosome appears to be RNA-dependent (11). The P element regulates odorant receptor choice. Such diversity/specificity could be very important in the cell's response to different signals or stresses and the consequent responses. The helicase-like transcription factor (HLTF) in cancer: loss of function or oncomorphic conversion of a tumor suppressor? Further Exploration Concept Links for. for p68 (70). Additionally, RHA has been found to be associated with the survival motor neuron protein (SMN), in Gems (nuclear bodies that are often associated with Cajal bodies) and in cytoplasmic spliceosomal small nuclear ribonucleoprotein complexes (snRNPs) suggesting a possible involvement for RHA in the assembly of spliceosomes (34). The gene encoding DDX3X is located on the X-chromosome, but escapes X-inactivation. Moreover, it reveals how silencing Hltf disrupts cell cycle progression, and attenuates DNA damage repair. Again the interaction was shown to occur through the C-terminal domain of DP97 but, in this case, was found to result in transcriptional repression of ER-regulated genes. Cell Mol Life Sci. Yan X., Mouillet J.F., Ou Q., Sadovsky Y. Aside from being expressed in mouse brain during embryonic and postnatal development, little is known about Hltf's functional importance. It is therefore tempting to speculate that p68, by virtue of its interactions with components of the transcriptional machinery (64,66) and with U1 snRNA at the 5 splice site (99), could act as a coupling factor between transcription and pre-mRNA processing. NCI CPTC Antibody Characterization Program, Sheridan PL, Schorpp M, Voz ML, Jones KA (1995) Cloning of an SNF2/SWI2-related protein that binds specifically to the SPH motifs of the SV40 enhancer and to the HIV-1 promoter. and transmitted securely. RH70, a bidirectional RNA helicase, co-purifies with U1snRNP. Similarly, RNA helicase activity did not appear to be required for p68 and p72 to function as transcriptional repressors (71). J Photochem Photobiol B. DExD/H box RNA helicases: multifunctional proteins with important roles Amplicons were subcloned and sequenced . The multiple nuclear functions of BRCA1: transcription, ubiquitination and DNA repair. -, Ding H, Descheemaeker K, Marynen P, Nelles L, Carvalho T, et al. Careers, Unable to load your collection due to an error. Ozgenc A., Loeb L.A. Current advances in unraveling the function of the Werner syndrome protein. The Drosophila P68 RNA helicase regulates transcriptional deactivation by promoting RNA release from chromatin. Proudfoot N.J., Furger A., Dye M.J. Interestingly, a study investigating proteins associating with the Drosophila fragile X protein, FMR1, has shown that the Drosophila p68 homologue (Dmp68/RM62) co-purifies with FMR1 and Argonaute 2 (a component of the RNA-induced silencing complex) and is required for RNAi (63), suggesting another potential function for p68. Tetsuka T., Uranishi H., Sanda T., Asamitsu K., Yang J.P., Wong-Staal F., Okamoto T. RNA helicase A interacts with nuclear factor kappaB p65 and functions as a transcriptional coactivator. Scale bar, 100 m. Godbout R., Squire J. Amplification of a DEAD box protein gene in retinoblastoma cell lines. Silencing of RNA helicase II/Gu inhibits mammalian ribosomal RNA production. In fact such a suggestion was made by Auboeuf et al. Moreover, the finding that overexpression of a fragment of RHA that is known to bind to BRCA1 gives a dominant negative mutant and causes defects in ploidy and cytokinesis in mammary epithelial cells suggests a possible co-suppressor function for RHA (84). They play essential roles in DNA replication, DNA repair, and DNA recombination in all organisms. However, direct evidence for an RNA helicase role has been somewhat elusive. Exons are numbered green rectangles. The functions of the conserved motifs are as follows: Motifs Q, I, II and VI are required for ATP binding and hydrolysis; motifs Ia, Ib, III, IV and V are thought to be involved in RNA binding. The .gov means its official. They are key players in every cellular process involving RNA or DNA. Kwek K.Y., Murphy S., Furger A., Thomas B., O'Gorman W., Kimura H., Proudfoot N.J., Akoulitchev A. U1 snRNA associates with TFIIH and regulates transcriptional initiation. Panel A, diagram showing the presence (wild-type) and absence (Hltf null) of sequences encoding the NLS, and a DNAnexus genome browser screen shot of RNA-seq data verifying deletion of the sequences from Hltf null transcripts. Importantly, for most of the proteins discussed above, the regions interacting with transcription factors and involved in transcriptional regulation lie in the N- or C-terminal domains outside the conserved helicase core. It is the best-characterized RNA helicase in translation initiation . No Hltf is detected in the brains of Hltf null mice by Western blot regardless of the exposure time. 2AFig. Active disruption of an RNAprotein interaction by a DExH/D RNA helicase. sharing sensitive information, make sure youre on a federal Before 2006 Aug 1;84(2):150-60. doi: 10.1016/j.jphotobiol.2006.02.010. Nakagawa Y., Morikawa H., Hirata I., Shiozaki M., Matsumoto A., Maemura K., Nishikawa T., Niki M., Tanigawa N., Ikegami M., et al. 2010;587:85-98. doi: 10.1007/978-1-60327-355-8_6. An interesting point from the studies of p68/p72 as transcriptional coactivators/repressors was the finding that, in most cases, RNA helicase activity was not required for their function in transcriptional regulation. DExH-Box helicase 9 (DHX9), also known as RNA helicase A (RHA), belongs to the DExD/H-Box superfamily II of helicases [ 1 ]. The .gov means its official. Schwer B. Yes, helicase was the enzyme that makes the DNA to unwinds its strands by breaking the Hydrogen bonds . Helicases as transcription termination factors: Different solutions for Although this study examined the role of p68 in transcript clearance for gene deactivation, it is also possible that p68 may play such a role to ensure efficient promoter clearance to increase efficiency of transcription. Splice variant quantification of wild-type neonatal (6-8 hour postpartum) brain gave a ratio of 5:1 for Hltf isoform 1 (exons 1-25) to isoform 2 (exons 1-21 with exon 21 extended via a partial intron retention event). The maleless protein associates with the X chromosome to regulate dosage compensation in, Richter L., Bone J.R., Kuroda M.I. To further understand the role of RHA on gene expression, we have identified a 50-amino-acid . R. Significant decreases (red thermometers=negative effects) in transcript expression of major components of the G2/M transition in Hltf null brain are superimposed on the proprietary multicomponent canonical pathway map from the MetaCore database [Straight lines=interactions; Symbols=events; +P=phosphorylation; B=binding; GR=group relation; CS=complex subunit. Zhang S., Grosse F. Nuclear DNA helicase II unwinds both DNA and RNA. 12. Thus DP103 repression of Egr2-mediated transcriptional activation exhibits promoter specificity and is at least in part dependent on HDAC recruitment. The site is secure. Clipboard, Search History, and several other advanced features are temporarily unavailable. In this review I shall concentrate on RNA helicase A (Dhx9), DP103 (Ddx20), p68 (Ddx5) and p72 (Ddx17), proteins for which there is a strong body of evidence showing that they play important roles in transcription, often as coactivators or corepressors through their interaction with key components of the transcriptional machinery, such as CREB-binding protein, p300, RNA polymerase II and histone deacetylases. Again DP103 was shown to repress Egr2-mediated transcriptional activation; however, this was not observed for all Egr2-responsive promoters, suggesting that this repression activity depended on the promoter context. Overexpression of rck/p54, a DEAD box protein, in human colorectal tumours. This activity is specific for p68 since RNAi suppression of p72 had no effect on the induction of p53 transcriptional activity by DNA damage. The human RNA helicase A (DDX9) gene maps to the prostate cancer susceptibility locus at chromosome band 1q25 and its pseudogene (DDX9P) to 13q22, respectively. Hltf's most important role is in the G2/M transition of the cell cycle (p = 4.672e-7) with an emphasis on transcript availability of major components in chromosome cohesion and condensation. 2023 Feb 6;24(4):3181. doi: 10.3390/ijms24043181. Wan C, Mahara S, Sun C, Doan A, Chua HK, Xu D, Bian J, Li Y, Zhu D, Sooraj D, Cierpicki T, Grembecka J, Firestein R. Sci Adv. RNA helicase A interacts with dsDNA and topoisomerase II. RNA helicases can have a variety of biochemical effects, such as unwinding or. p72 (Ddx17) was fortuitously isolated from an antibody screen of a HeLa expression library and was found to have remarkable similarity to p68, sharing 90% amino acid sequence identity over the conserved core (49), although the N- and C-termini are significantly different. This protein has been shown to be associated both with the transcriptional machinery (64,66) and with spliceosomes (55), and to specifically interact with the U1 snRNA at the 5 splice site (56,99); moreover, it has been demonstrated to function in transcriptional initiation and pre-mRNA splicing (56,70). The number of amino acids in the helicase cores and the N- and C-terminal domains are indicated for each protein. 2016 Jan 13;80(1):139-60. doi: 10.1128/MMBR.00055-15. The function of DExD/H box proteins in transcriptional regulation is likely to be dependent on interacting transcription factors, the signals they respond to, the promoter context and the cellular environment. Ford M.J., Anton I.A., Lane D.P. These findings have led to the suggestion that DExD/H proteins may regulate transcription either by acting as nucleating factors to recruit transcription factors and other coregulators to the transcriptional initiation complex or by stabilizing the initiation complex through interactions with multiple factors in the complex (Figure 2). Dual Roles of RNA Helicase A in CREB-Dependent Transcription In addition to their role as transcriptional coactivators, p68 and p72 have been shown to have other functions as transcriptional repressors: both proteins have been shown to interact with HDAC1 and to exhibit intrinsic promoter-specific transcriptional repressor activity when tethered to DNA using the GAL4 system (71). The finding that p68 coactivated ER function (64) not only demonstrated for the first time a role for p68 in transcriptional regulation but also highlighted a potential link with tumour development. Expression of the DEAD box RNA helicase p68 is developmentally and growth regulated and correlates with organ differentiation/maturation in the fetus. Mfd is a bacterial monomeric RecG-like SF2 helicase that plays a crucial role in transcription-coupled repair, one of the two main pathways for nucleotide-excision DNA repair. Initially identified as basal transcription factor, TFIIH also participates in transcription regulation and plays a key role in nucleotide excision repair (NER) for opening DNA at damaged sites, lesion verification and recruitment of additional repair factors. p68/p72 could thus also enhance transcriptional activity by recruiting RNA Pol II to the initiation complex or by stabilizing the complex. Genomatics (Munich, Germany) used our data to generate a weight matrix available in MatInspector .
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