Panel A, immunostained coronal section from, Figure 5. Structure and Mechanisms of SF1 DNA Helicases. Furthermore RNAi suppression of p68 inhibited the expression of p53 target genes in response to DNA damage and p53-dependent apoptosis, suggesting a requirement for p68 in the p53 response (70). Front Neurosci. DP103 (Ddx20) was originally isolated as a DEAD box protein that associated with the EpsteinBarr virus nuclear proteins EBNA2 and EBNA3C, which play a role in the regulation of transcription of both latent viral and cellular genes (37). Federal government websites often end in .gov or .mil. Guzder SN, Sung P, Bailly V, Prakash L, Prakash S. Nature. Helicases can be classified as RNA or DNA helicases based on the substrate they bind and remodel. Helicases: an overview - PubMed Absence of Dbp2p alters both nonsense-mediated mRNA decay and rRNA processing. Nuclear protein with sequence homology to translation initiation factor eIF-4A. Virus Res. Panel C, comparatively strong immunostaining in what appear to be secondary spermatocytes and leydig cells (40X) was well as spermatids (40X inset) in seminiferous tubules from newborn control mice. PMC Clipboard, Search History, and several other advanced features are temporarily unavailable. In transcription termination, the hairpin causes the RNA polymerase to stall and the transcript to separate from the DNA. Rowell S., Newman B., Boyd J., King M.C. See also Figures S1 and S2. RNA helicases are involved in shaping the form of RNA molecules, during all processes involving RNA, such as transcription, splicing, and translation. 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. Concrete evidence that RHA (Dhx9) played an active role in transcription came from the findings of Nakajima et al. Rajendran R.R., Nye A.C., Frasor J., Balsara R.D., Martini P.G., Katzenellenbogen B.S. O'Gorman W., Kwek K.Y., Thomas B., Akoulitchev A. Non-coding RNA in transcription initiation. RHA is also a component of holo-RNA polymerase II (Pol II) complexes and recruits Pol II to the CREB binding protein (CBP). This is particularly relevant since it is clear that mRNA processing events (cap formation, splicing and 3 end formation/polyadenylation) occur co-transcriptionally [reviewed in (97,98)]. 2013;767:17-46. doi: 10.1007/978-1-4614-5037-5_2. Addition . . See this image and copyright information in PMC. Unlike replicative helicases, the DEAD and DExH box helicases involved in translation initiation cannot processively unwind long duplexes and appear to have a different mode of unwinding [41], [42], [43], [44].The helicase activity is mediated by binding to RNA in the presence of ATP, followed by cycles of ATP hydrolysis, release of the helicase from the RNA . Causevic M., Hislop R.G., Kernohan N.M., Carey F.A., Kay R.A., Steele R.J., Fuller-Pace F.V. Myohanen S., Baylin S.B. government site. 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). Ohtani N., Yamakoshi K., Takahashi A., Hara E. The p16INK4a-RB pathway: molecular link between cellular senescence and tumor suppression. PCR amplification of DNA fragments. HHS Vulnerability Disclosure, Help role of DNA helicases and their interaction partners in genome This is reminiscent of the findings for DP103 (45). p72 and its alternative translation initiation product p82 have themselves been shown to have RNA helicase activity in vitro (50,51) and p68 and p72 were subsequently shown to exist as heterodimers in cells (52). In fact such a suggestion was made by Auboeuf et al. Deriving energy from ATP hydrolysis, helicases alter the structure of DNA, RNA, or DNA:RNA duplexes, remodeling chromatin and modulating access to the DNA template by the transcriptional machinery. Introduction. RHA has also been shown to interact with the promoters of the MDR1 and p16INK4A genes; therefore these are also indicated. FOIA DExH-Box helicase 9 (DHX9), also known as RNA helicase A (RHA), belongs to the DExD/H-Box superfamily II of helicases [ 1 ]. None declared. 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. 1994 Jun 16;369(6481):578-81. doi: 10.1038/369578a0. Federal government websites often end in .gov or .mil. Auboeuf D., Honig A., Berget S.M., O'Malley B.W. Ares M.Jr, Proudfoot N.J. Co-expression of p68 potently stimulated transcription from p53-responsive promoters. 1,650 likes, 16 comments - worldofmedics (@world_of_medics) on Instagram: " Helicase: The zipper. The maleless protein associates with the X chromosome to regulate dosage compensation in, Richter L., Bone J.R., Kuroda M.I. Helicase . Regulation of alternative splicing by the ATP-dependent DEAD-box RNA helicase p72. official website and that any information you provide is encrypted Zhong X., Safa A.R. Such diversity/specificity could be very important in the cell's response to different signals or stresses and the consequent responses. Panel A, diagram showing the presence (wild-type) and absence. 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. Secondly, DP103 was found to interact with the early growth response 2 (Egr2/Krox-20) transcription factor, which is important for myelination of the peripheral nervous system and for establishing segmentation in the developing vertebrate hindbrain (45). BRCA1 protein is linked to the RNA polymerase II holoenzyme complex via RNA helicase A. Miki Y., Swensen J., Shattuck-Eidens D., Futreal P.A., Harshman K., Tavtigian S., Liu Q., Cochran C., Bennett L.M., Ding W., et al. Detection of a novel ATP-dependent cross-linked protein at the 5 splice site-U1 small nuclear RNA duplex by methylene blue-mediated photo-cross-linking. Zhou K., Choe K.T., Zaidi Z., Wang Q., Mathews M.B., Lee C.G. 2006 Aug 1;84(2):150-60. doi: 10.1016/j.jphotobiol.2006.02.010. In Escherichia coli, about half of the transcription events are terminated The spanish connection: transcription and mRNA processing get even closer. In addition to Cap-H2, Condensin II has Cap-D3 and Cap-G2. R-loop proximity proteomics identifies a role of DDX41 in transcription Hirling H., Scheffner M., Restle T., Stahl H. RNA helicase activity associated with the human p68 protein. They play essential roles in DNA replication, DNA repair, and DNA recombination in all organisms. The ZBD acts as an anchor domain for the binding of different transcription factors in regulating transcription initiation, recycling and termination processes. Campbell L., Hunter K.M., Mohaghegh P., Tinsley J.M., Brasch M.A., Davies K.E. Panel A, Hltf binds to the ACTTTT sequence in the P-element located between Olfr 713 and Olfr 714 on chromosome 7 . Lamm G.M., Nicol S.M., Fuller-Pace F.V., Lamond A.I. MeSH Other members of the DExD/H family shown to act as transcriptional regulators include the DEVD subfamily protein RHII/Gu (Ddx21) and the DEAD subfamily protein DP97 (Ddx54). In a subsequent study, Aratani et al. DNA Helicase: Definition, Role & Function - Study.com This protein was also independently isolated as Gemin3, a protein that interacts with SMN and is a component of the SMN complex in nuclear Gems (38), suggesting a role for Gemin3 in snRNP assembly. As with RHA the unique C-terminus of Gemin3 was required for interaction with SMN. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). The p68 and p72 DEAD box RNA helicases interact with HDAC1 and repress transcription in a promoter-specific manner. Colors for lines and symbols are green for positive, and gray for unspecified]. Many of the studies that have demonstrated roles for these proteins in transcription have shown that they function through interaction with transcriptional coactivators/corepressors. 2018 Jul 5;13(7):e0200211. I shall also briefly review evidence that highlights roles for DExD/H box proteins in regulating transcription of genes important in cell proliferation, cell cycle arrest or apoptosis. Unraveling the role of helicases in transcription - PubMed Sumoylation often correlates with transcriptional repression, which, at least in some cases, is mediated through HDAC recruitment (46). the contents by NLM or the National Institutes of Health. Ip F.C., Chung S.S., Fu W.Y., Ip N.Y. Developmental and tissue-specific expression of DEAD box protein p72. Accessibility The murine DP103 homologue was identified in a yeast two-hybrid screen as a protein that interacted with the proximal transcriptional repression domain within the nuclear steroidogenic factor SF-1, an orphan nuclear receptor that regulates expression of genes essential for reproductive and endocrine development (40). Studies to examine the roles of DExD/H box proteins in the formation and modulation of transcription and splicing complexes should help to elucidate possible mechanisms by which these proteins could couple these different processes. However, not all physiological target promoters of SF-1 tested were repressed, suggesting a measure of promoter specificity in repression by DP103 (41). 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. Panel A, each point is the mean of three replicate RPKM values for an individual gene in control brain plotted against values of the corresponding gene in Hltf null brain. 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. Summary of the commonly used names and reported functions for RHA, DP103, p68 and p72. Integrating mRNA processing with transcription. Fairman M.E., Maroney P.A., Wang W., Bowers H.A., Gollnick P., Nilsen T.W., Jankowsky E. Protein displacement by DExH/D RNA helicases without duplex unwinding. The ATPase and/or helicase activity of RHA is required for CREB-dependent transcription. In the case of p53, a helicase inactive mutant of p68 was able to stimulate p53 transcriptional activity as efficiently as the wild-type protein (70). Helicases as transcription termination factors: Different solutions for Yang H., Zhou J., Ochs R.L., Henning D., Jin R., Valdez B.C. -, Zhang Q, Ekhterae D, Kim KH (1997) Molecular cloning and characterization of P113, a mouse SNF2/SWI2-related transcription factor. The DEXD/H-box RNA helicase RHII/Gu is a co-factor for c-Jun-activated transcription. Activation of gene expression by ER is mediated by two autonomous transcription activation domains, AF1 and AF2. Liu Z.R. General and Target-Specific DExD/H RNA Helicases in Eukaryotic RNA helicases - PMC - National Center for Biotechnology Information The .gov means its official. for p68 (70). Godbout R., Squire J. Amplification of a DEAD box protein gene in retinoblastoma cell lines. 2021 Sep;99(9):1209-1220. doi: 10.1007/s00109-021-02083-1. 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). 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. DNA helicases involved in DNA repair and their roles in cancer and transmitted securely. An RNA-Seq snapshot of the neonatal brain transcriptome showed 341 of 20,000 transcripts were altered (p < 0.05) - 95 up regulated and 246 down regulated. What Is The Role Of Dna Helicase In The Replication Of Dna? Helicase - an overview | ScienceDirect Topics Moreover, it has been suggested that the interaction of DP103 with the EpsteinBarr virus proteins EBNA2 and EBNA3C (37) may interfere with the METS/DP103 interaction and may contribute to transformation by this virus (44). Careers. Schlegel B.P., Starita L.M., Parvin J.D. No, you're not wrong. RHII/Gu was first isolated as a nucleolar protein recognized by an autoantibody from a patient with watermelon stomach disease (73). 2020 Nov;95:102943. doi: 10.1016/j.dnarep.2020.102943. (1996) Characterization of a helicase-like transcription factor involved in the expression of the human plasminogen activator inhibitor-1 gene. Aside from being expressed in mouse brain during embryonic and postnatal development, little is known about Hltf's functional importance. Schwer B. Lee C.G., Chang K.A., Kuroda M.I., Hurwitz J. 10.1002/(SICI)1521-1878(199808)20:8<634::AID-BIES6>3.0.CO;2-I. The findings discussed above highlight a very clear role for RHA in transcriptional regulation. Additionally, the idea that these proteins may act as adaptor molecules to facilitate the formation, or improve the stability, of specific protein complexes involved in transcription regulation would allow them to have different functions in the cell, depending on other factors present or the signals to which the cell responds. 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. Ribosomes, Transcription, Translation | Learn Science at Scitable - Nature 2016 Jan;73(1):129-47. doi: 10.1007/s00018-015-2060-6. Hence females have two active copies and males only . Transcription is the first step in decoding a cell . Hltf expression in null and control brains. 2008 Feb;65(4):591-604. doi: 10.1007/s00018-007-7392-4. Moreover this domain was found to possess an autonomous intrinsic transcriptional repression activity and to repress the activation function of SF-1 (41). As mutants in RecQ family genes have unstable chromosomes, it was proposed that members of the RecQ helicase family play a central role in the maintenance of genomic stability and thereby the prevention of tumorigenesis. and transmitted securely. A tRNA contains hairpins as well, though the hairpins play different roles in the two cases. PLoS One. An induced Ets repressor complex regulates growth arrest during terminal macrophage differentiation. Hltf expression in null and control tissues. official website and that any information you provide is encrypted This last facet, translation, is an intricate process that involves DDX/DHX helicases and presents a regulatory node that is highly targetable. Lee C.G., Reichman T.W., Baik T., Mathews M.B. Rossow K.L., Janknecht R. Synergism between p68 RNA helicase and the transcriptional coactivators CBP and p300. Helmer RA, Martinez-Zaguilan R, Kaur G, Smith LA, Dufour JM, Chilton BS. Henning D., So R.B., Jin R., Lau L.F., Valdez B.C. Moreover, it reveals how silencing Hltf disrupts cell cycle progression, and attenuates DNA damage repair. Prokaryotic and eukaryotic DNA helicases - PMC - National Center for Palmiter R.D., Sandgren E.P., Avarbock M.R., Allen D.D., Brinster R.L. Their prominence is marked by various cancers and genetic disorders that are linked to helicase defects. The interaction with SF-1 again was shown to occur through the C-terminal domain of DP103, outside the conserved helicase core (Figure 1). eCollection 2018. Moreover such functions, as is the case for the known role for p68 in splicing (56), may require a helicase-active protein, in contrast to its role in transcriptional initiation (64,70). This study went on to show that the C-terminal domain of RHII/Gu interacts with the N-terminal transactivation domain of c-Jun, a transcription factor which plays a key role in the response of cells to stress, apoptotic and differentiation signals. On the other hand the intrinsic transcriptional repression function of DP103 appears to be HDAC-independent, suggesting that there is more than one mechanism for transcriptional repression by DP103. 2010;587:1-12. doi: 10.1007/978-1-60327-355-8_1. Firstly, it was found to interact with the N-terminal repression domain of the mitogenic Ets repressor METS [a member of the ETS-domain transcription factor family (43)], which is induced during macrophage differentiation and represses transcription of Ets target genes involved in Ras-dependent proliferation (44). 2.1 TFIIH composition: 10 subunits and more TFIIH was initially identified using an in vitro transcription run-off assay as a factor, which together with TFIIA, -IIB, -IID, -IIE, and -IIF is required for initiation of transcription of protein coding genes by RNA polymerase II. 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. DExD/H proteins have long been known to function as part of large RNP complexes in processes such as pre-mRNA processing, translation initiation and ribosome assembly (2). Zhang S., Grosse F. Nuclear DNA helicase II unwinds both DNA and RNA. In Hltf null brain, the functional architecture of each complex is jeopardized by reduced availability (pale shading) of transcripts for major protein components. Abstract - DNA helicases are enzymes that are able to unwind DNA by the use of the energy-equivalent ATP. J Biol Chem 270: 45754587. MeSH Hartman T.R., Qian S., Bolinger C., Fernandez S., Schoenberg D.R., Boris-Lawrie K. RNA helicase A is necessary for translation of selected messenger RNAs. The ATPase and/or helicase activity of RHA is required for CREB-dependent transcription. Hltf also regulates Smad7/Bambi/Tgf-beta/Bmp5/Wnt10b signaling in brain. Ogilvie V.C., Wilson B.J., Nicol S.M., Morrice N.A., Saunders L.R., Barber G.N., Fuller-Pace F.V. Gillian A.L., Svaren J. PMC Metivier R., Penot G., Hubner M.R., Reid G., Brand H., Kos M., Gannon F. Estrogen receptor-alpha directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter. Inclusion in an NLM database does not imply endorsement of, or agreement with, The DEAD box protein DP103 is a regulator of steroidogenic factor-1. Unable to load your collection due to an error, Unable to load your delegates due to an error. DNA helicases involved in DNA repair and their roles in cancer Helicase-like transcription factor-deletion from the tumor microenvironment in a cell line-derived xenograft model of colorectal cancer reprogrammed the human transcriptome-S-nitroso-proteome to promote inflammation and redirect metastasis. Heterologous introns can enhance expression of transgenes in mice. Dev Biol 183: 166182. Lee C.G., Hurwitz J. although they appear to play regulatory roles in . To further . Cohesin/condensin contain structural maintenance of, Figure 7. In vivo models, particularly mice, have been used to interrogate helicase function and serve as . Functional interaction between RNA helicase II/Gu(alpha) and ribosomal protein L4. Proteins with seven conserved "helicase domains" play essential roles in all aspects of nucleic acid metabolism. Additionally, the recently suggested functions for the p68 Drosophila homologue in transcript clearance and export (72) could imply a further function for p68 in ensuring that the synthesized mRNA is efficiently exported away from promoter sites. Epub 2006 Apr 19. Aside from being expressed in mouse brain during embryonic and postnatal development, little is known about Hltf's functional importance. Proudfoot N.J., Furger A., Dye M.J. Since DP103 had been shown to interact with HDAC2 and HDAC5, Gillian and Svaren (45) tested the effect of the HDAC inhibitor Trichostatin A (TSA) on the ability of DP103 to repress transcription. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. These N- and C-terminal domains through interaction with different partners would also provide the capability for their involvement in multiple processes. p72: a human nuclear DEAD box protein highly related to p68. Buszczak M., Spradling A.C. Roles of eukaryotic topoisomerases in transcription - Nature Funding to pay the Open Access publication charges for this article was provided by Tenovus Scotland. Yang H., Henning D., Valdez B.C. There are many helicases, representing the great variety of processes in which strand separation must be catalyzed. Addition of the 67.5-kDa nsp13 helicase to the RNA-bound holo-RdRp sample forms a transcription complex/helicase assembly with 1:1 stoichiometry (top). -, Ding H, Descheemaeker K, Marynen P, Nelles L, Carvalho T, et al. Furger A., O'Sullivan J.M., Binnie A., Lee B.A., Proudfoot N.J. Complete loss of Hltf caused encephalomalacia with increased apoptosis, and reduced viability. They play essential roles in DNA replication, DNA repair, and DNA recombination in all organisms. 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 finding that p68 was one of the proteins co-purifying with spliceosomes in a mass spectrometric analysis of spliceosomal complexes (55) suggested a role for this protein in RNA splicing. Colantoni A, Capauto D, Alfano V, D'Ambra E, D'Uva S, Tartaglia GG, Morlando M. Int J Mol Sci. 2016 Jan 13;80(1):139-60. doi: 10.1128/MMBR.00055-15. p68 was also found to be recruited to p53-responsive promoters in response to DNA damage (70) echoing the finding for p68/ER in response to estrogen (69) and suggesting that p68 may play a role in transcriptional initiation, perhaps through facilitating the recruitment of other transcription factors or coactivators through its interaction with factors such as CBP, p300, SRC1 and RNA Pol II (6466). A subset of nuclear receptor coregulators act as coupling proteins during synthesis and maturation of RNA transcripts. This is indicated in Figure 2C for p68 and its yeast homologue Dbp2, which was shown to be important in rRNA processing and nonsense mediated mRNA decay (58). Interestingly p72 was also found to co-purify with U1 snRNP (57). 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. Helicases: amino acid sequence comparisons and structurefunction relationships. In recent years, many laboratories have characterized the specialized roles of helicase to resolve transcription-replication conflicts, maintain telomeres, mediate cell cycle checkpoints, remodel stalled replication forks, and regulate transcription. Southern analysis was performed with DNA digested with Asp1-Stu1, blotted on nylon membrane, and hybridized with the 3- probe detecting the Asp1-Stu1-fragments of expected sizes (kb). However, there is also a strong body of evidence showing that RHA is involved in the expression/nuclear export of retroviral RNAs and in pre-mRNA processing. RNA helicases can have a variety of biochemical effects, such as unwinding or. Figure 3. Epub 2020 Aug 15. Tang H., Gaietta G.M., Fischer W.H., Ellisman M.H., Wong-Staal F. A cellular cofactor for the constitutive transport element of type D retrovirus. 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. Yan X., Mouillet J.F., Ou Q., Sadovsky Y. 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. helicase medicine target tumor Helicase proteins have a diverse range of cellular functions that stem from their ability to resolve and remodel DNA and RNA structures. DDX3X is an RNA helicase with many functions in RNA metabolism such as mRNA translation, alternative pre-mRNA splicing and mRNA stability, but also plays a role as a regulator of transcription as well as in the Wnt/beta-catenin- and Nf-B signaling pathways. Modular domain structure of RNA helicases. 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 . The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Some examples are discussed below. 8600 Rockville Pike Panel E, Western blot of immunoprecipitates shows the absence of Hltf protein from tissues from Hltf null mice compared with K-562 cells (robust, positive control for 115-kDa human Hltf). Mol Endocrinol 10: 13351349. I thank Patrick Linder for his insight into DExD/H proteins and his support, and Simak Ali and David Meek for helpful comments on the manuscript. Expression and function of Smad7 in autoimmune and inflammatory diseases. Brinster R.L., Allen J.M., Behringer R.R., Gelinas R.E., Palmiter R.D. Roles for DEAD (and DExH) box proteins in pre-mRNA and pre-rRNA processing have been well documented (2,62).