A highly ordered, nonprotective MALAT1 ENE structure is adopted prior to triplex formation

Yonkunas, Michael J.; Baird, Nathan J.

doi:10.1261/rna.069906.118

A highly ordered, nonprotective MALAT1 ENE structure is adopted prior to triplex formation

Journal Article · Tue May 21 00:00:00 EDT 2019 · RNA

DOI:https://doi.org/10.1261/rna.069906.118· OSTI ID:1575027

Yonkunas, Michael J. ^[1]; ^[1]

University of the Sciences, Philadelphia, PA (United States)

The 3' end of the ~7 kb lncRNA MALAT1 contains an evolutionarily and structurally conserved element for nuclear expression (ENE) which confers protection from cellular degradation pathways. Formation of an ENE triple helix is required to support transcript accumulation, leading to persistent oncogenic activity of MALAT1 in multiple cancer types. Though the specific mechanism of triplex-mediated protection remains unknown, the MALAT1 ENE triplex has been identified as a promising target for therapeutic intervention. Interestingly, a maturation step of the nascent lncRNA 3' end is required prior to triplex formation. We hypothesize that disruption of the maturation or folding process may be a viable mechanism of inhibition. To assess putative cotranscriptional ENE conformations prior to triplex formation, we perform microsecond MD simulations of a partially folded ENE conformation and the ENE triplex. Herein, we identify a highly ordered ENE structure prior to triplex formation. Extensive formation of U•U base pairs within the large U-rich internal loops produces a global rod-like architecture. We present a three-dimensional structure of the isolated ENE motif, the global features of which are consistent with small angle X-ray scattering (SAXS) experiments. Our structural model represents a nonprotective conformation of the MALAT1 ENE, providing a molecular description useful for future mechanistic and inhibition studies. We anticipate that targeting stretches of U•U pairs within the ENE motif will prove advantageous for the design of therapeutics targeting this oncogenic lncRNA.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1575027

Journal Information:: RNA, Journal Name: RNA Journal Issue: 8 Vol. 25; ISSN 1355-8382

Publisher:: Cold Spring Harbor Laboratory PressCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

References (52)

Discovery of Small Molecule Ligands for MALAT1 by Tuning an RNA-Binding Scaffold Donlic, Anita; Morgan, Brittany S.; Xu, Jason L. Angewandte Chemie International Edition, Vol. 57, Issue 40 https://doi.org/10.1002/anie.201808823	journal	September 2018
Structure, dynamics, and elasticity of free 16s rRNA helix 44 studied by molecular dynamics simulations Réblová, Kamila; Lankas̆, Filip; Rázga, Filip Biopolymers, Vol. 82, Issue 5 https://doi.org/10.1002/bip.20503	journal	August 2006
Bifacial PNA Complexation Inhibits Enzymatic Access to DNA and RNA Xia, Xin; Piao, Xijun; Fredrick, Kurt ChemBioChem, Vol. 15, Issue 1 https://doi.org/10.1002/cbic.201300536	journal	November 2013
Long non-coding RNA MALAT-1 overexpression predicts tumor recurrence of hepatocellular carcinoma after liver transplantation Lai, Ming-chun; Yang, Zhe; Zhou, Lin Medical Oncology, Vol. 29, Issue 3 https://doi.org/10.1007/s12032-011-0004-z	journal	June 2011
Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes Ryckaert, Jean-Paul; Ciccotti, Giovanni; Berendsen, Herman J. C. Journal of Computational Physics, Vol. 23, Issue 3 https://doi.org/10.1016/0021-9991(77)90098-5	journal	March 1977
VMD: Visual molecular dynamics Humphrey, William; Dalke, Andrew; Schulten, Klaus Journal of Molecular Graphics, Vol. 14, Issue 1 https://doi.org/10.1016/0263-7855(96)00018-5	journal	February 1996
Convergence and reproducibility in molecular dynamics simulations of the DNA duplex d(GCACGAACGAACGAACGC) Galindo-Murillo, Rodrigo; Roe, Daniel R.; Cheatham, Thomas E. Biochimica et Biophysica Acta (BBA) - General Subjects, Vol. 1850, Issue 5 https://doi.org/10.1016/j.bbagen.2014.09.007	journal	May 2015
Chain Length Determines the Folding Rates of RNA Hyeon, Changbong; Thirumalai, D. Biophysical Journal, Vol. 102, Issue 3 https://doi.org/10.1016/j.bpj.2012.01.003	journal	February 2012
3′ End Processing of a Long Nuclear-Retained Noncoding RNA Yields a tRNA-like Cytoplasmic RNA Wilusz, Jeremy E.; Freier, Susan M.; Spector, David L. Cell, Vol. 135, Issue 5 https://doi.org/10.1016/j.cell.2008.10.012	journal	November 2008
A Decade of Riboswitches Serganov, Alexander; Nudler, Evgeny Cell, Vol. 152, Issue 1-2 https://doi.org/10.1016/j.cell.2012.12.024	journal	January 2013
Conservation of a Triple-Helix-Forming RNA Stability Element in Noncoding and Genomic RNAs of Diverse Viruses Tycowski, Kazimierz T.; Shu, Mei-Di; Borah, Sumit Cell Reports, Vol. 2, Issue 1 https://doi.org/10.1016/j.celrep.2012.05.020	journal	July 2012
Myriad Triple-Helix-Forming Structures in the Transposable Element RNAs of Plants and Fungi Tycowski, Kazimierz T.; Shu, Mei-Di; Steitz, Joan A. Cell Reports, Vol. 15, Issue 6 https://doi.org/10.1016/j.celrep.2016.04.010	journal	May 2016
Structural Transitions and Thermodynamics of a Glycine-Dependent Riboswitch from Vibrio cholerae Lipfert, Jan; Das, Rhiju; Chu, Vincent B. Journal of Molecular Biology, Vol. 365, Issue 5 https://doi.org/10.1016/j.jmb.2006.10.022	journal	February 2007
Role of the Adenine Ligand on the Stabilization of the Secondary and Tertiary Interactions in the Adenine Riboswitch Priyakumar, U. Deva; MacKerell, Alexander D. Journal of Molecular Biology, Vol. 396, Issue 5 https://doi.org/10.1016/j.jmb.2009.12.024	journal	March 2010
The Speed of RNA Transcription and Metabolite Binding Kinetics Operate an FMN Riboswitch Wickiser, J. Kenneth; Winkler, Wade C.; Breaker, Ronald R. Molecular Cell, Vol. 18, Issue 1 https://doi.org/10.1016/j.molcel.2005.02.032	journal	April 2005
Kinetics and Thermodynamics Make Different Contributions to RNA Folding In Vitro and in Yeast Mahen, Elisabeth M.; Harger, Jason W.; Calderon, Elise M. Molecular Cell, Vol. 19, Issue 1 https://doi.org/10.1016/j.molcel.2005.05.025	journal	July 2005
Identification of a Rapid Mammalian Deadenylation-Dependent Decay Pathway and Its Inhibition by a Viral RNA Element Conrad, Nicholas K.; Mili, Stavroula; Marshall, Eleanor L. Molecular Cell, Vol. 24, Issue 6 https://doi.org/10.1016/j.molcel.2006.10.029	journal	December 2006
Decapping of Long Noncoding RNAs Regulates Inducible Genes Geisler, Sarah; Lojek, Lisa; Khalil, Ahmad M. Molecular Cell, Vol. 45, Issue 3 https://doi.org/10.1016/j.molcel.2011.11.025	journal	February 2012
Therapeutic Targeting of Long Non-Coding RNAs in Cancer Arun, Gayatri; Diermeier, Sarah D.; Spector, David L. Trends in Molecular Medicine, Vol. 24, Issue 3 https://doi.org/10.1016/j.molmed.2018.01.001	journal	March 2018
Geometric nomenclature and classification of RNA base pairs Leontis, Neocles B.; Westhof, Eric RNA, Vol. 7, Issue 4 https://doi.org/10.1017/S1355838201002515	journal	April 2001
Ligand-Induced Stabilization of a Duplex-like Architecture Is Crucial for the Switching Mechanism of the SAM-III Riboswitch Suresh, Gorle; Srinivasan, Harini; Nanda, Shivani Biochemistry, Vol. 55, Issue 24 https://doi.org/10.1021/acs.biochem.5b00973	journal	June 2016
Frictional Effects on RNA Folding: Speed Limit and Kramers Turnover Hori, Naoto; Denesyuk, Natalia A.; Thirumalai, D. The Journal of Physical Chemistry B, Vol. 122, Issue 49 https://doi.org/10.1021/acs.jpcb.8b07129	journal	September 2018
Thermodynamics of Single Mismatches in RNA Duplexes ^† Kierzek, Ryszard; Burkard, Mark E.; Turner, Douglas H. Biochemistry, Vol. 38, Issue 43 https://doi.org/10.1021/bi991186l	journal	October 1999
Mimicking Co-Transcriptional RNA Folding Using a Superhelicase Hua, Boyang; Panja, Subrata; Wang, Yanbo Journal of the American Chemical Society, Vol. 140, Issue 32 https://doi.org/10.1021/jacs.8b03784	journal	July 2018
Expanding the functional role of long noncoding RNAs Johnsson, Per; Morris, Kevin V. Cell Research, Vol. 24, Issue 11 https://doi.org/10.1038/cr.2014.104	journal	August 2014
The emerging role of lncRNAs in cancer Huarte, Maite Nature Medicine, Vol. 21, Issue 11 https://doi.org/10.1038/nm.3981	journal	November 2015
Structure of an RNA double helix including uracil-uracil base pairs in an internal loop Baeyens, Katrien J.; De Bondt, Hendrik L.; Holbrook, Stephen R. Nature Structural Biology, Vol. 2, Issue 1 https://doi.org/10.1038/nsb0195-56	journal	January 1995
High-performance virtual screening by targeting a high-resolution RNA dynamic ensemble Ganser, Laura R.; Lee, Janghyun; Rangadurai, Atul Nature Structural & Molecular Biology, Vol. 25, Issue 5 https://doi.org/10.1038/s41594-018-0062-4	journal	May 2018
The yeast EDC1 mRNA undergoes deadenylation-independent decapping stimulated by Not2p, Not4p, and Not5p Muhlrad, Denise; Parker, Roy The EMBO Journal, Vol. 24, Issue 5 https://doi.org/10.1038/sj.emboj.7600560	journal	February 2005
A Kaposi's sarcoma virus RNA element that increases the nuclear abundance of intronless transcripts Conrad, Nicholas K.; Steitz, Joan A. The EMBO Journal, Vol. 24, Issue 10 https://doi.org/10.1038/sj.emboj.7600662	journal	April 2005
MALAT-1, a novel noncoding RNA, and thymosin β4 predict metastasis and survival in early-stage non-small cell lung cancer Ji, Ping; Diederichs, Sven; Wang, Wenbing Oncogene, Vol. 22, Issue 39 https://doi.org/10.1038/sj.onc.1206928	journal	September 2003
A large noncoding RNA is a marker for murine hepatocellular carcinomas and a spectrum of human carcinomas Lin, R.; Maeda, S.; Liu, C. Oncogene, Vol. 26, Issue 6 https://doi.org/10.1038/sj.onc.1209846	journal	July 2006
Molecular dynamics with coupling to an external bath Berendsen, H. J. C.; Postma, J. P. M.; van Gunsteren, W. F. The Journal of Chemical Physics, Vol. 81, Issue 8 https://doi.org/10.1063/1.448118	journal	October 1984
A simple ligand that selectively targets CUG trinucleotide repeats and inhibits MBNL protein binding Arambula, J. F.; Ramisetty, S. R.; Baranger, A. M. Proceedings of the National Academy of Sciences, Vol. 106, Issue 38 https://doi.org/10.1073/pnas.0901824106	journal	September 2009
Formation of triple-helical structures by the 3'-end sequences of MALAT1 and MEN noncoding RNAs Brown, J. A.; Valenstein, M. L.; Yario, T. A. Proceedings of the National Academy of Sciences, Vol. 109, Issue 47 https://doi.org/10.1073/pnas.1217338109	journal	November 2012
Exploring the folding landscape of a structured RNA Russell, R.; Zhuang, X.; Babcock, H. P. Proceedings of the National Academy of Sciences, Vol. 99, Issue 1 https://doi.org/10.1073/pnas.221593598	journal	December 2001
3DNA: a software package for the analysis, rebuilding and visualization of three-dimensional nucleic acid structures Lu, X. -J. Nucleic Acids Research, Vol. 31, Issue 17 https://doi.org/10.1093/nar/gkg680	journal	September 2003
Structural insights of non-canonical U•U pair and Hoogsteen interaction probed with Se atom Sheng, Jia; Gan, Jianhua; Soares, Alexei S. Nucleic Acids Research, Vol. 41, Issue 22 https://doi.org/10.1093/nar/gkt799	journal	September 2013
DSSR: an integrated software tool for dissecting the spatial structure of RNA Lu, Xiang-Jun; Bussemaker, Harmen J.; Olson, Wilma K. Nucleic Acids Research https://doi.org/10.1093/nar/gkv716	journal	July 2015
Finely tuned conformational dynamics regulate the protective function of the lncRNA MALAT1 triple helix Ageeli, Abeer A.; McGovern-Gooch, Kayleigh R.; Kaminska, Magdalena M. Nucleic Acids Research, Vol. 47, Issue 3 https://doi.org/10.1093/nar/gky1171	journal	November 2018
A triple helix stabilizes the 3' ends of long noncoding RNAs that lack poly(A) tails Wilusz, J. E.; JnBaptiste, C. K.; Lu, L. Y. Genes & Development, Vol. 26, Issue 21 https://doi.org/10.1101/gad.204438.112	journal	October 2012
Transcription elongation rate affects nascent histone pre-mRNA folding and 3′ end processing Saldi, Tassa; Fong, Nova; Bentley, David L. Genes & Development, Vol. 32, Issue 3-4 https://doi.org/10.1101/gad.310896.117	journal	February 2018
Determination of the regularization parameter in indirect-transform methods using perceptual criteria Svergun, D. I. Journal of Applied Crystallography, Vol. 25, Issue 4, p. 495-503 https://doi.org/10.1107/S0021889892001663	journal	August 1992
CRYSOL – a Program to Evaluate X-ray Solution Scattering of Biological Macromolecules from Atomic Coordinates Svergun, D.; Barberato, C.; Koch, M. H. J. Journal of Applied Crystallography, Vol. 28, Issue 6 https://doi.org/10.1107/S0021889895007047	journal	December 1995
Poly(A) Tail Recognition by a Viral RNA Element Through Assembly of a Triple Helix Mitton-Fry, R. M.; DeGregorio, S. J.; Wang, J. Science, Vol. 330, Issue 6008 https://doi.org/10.1126/science.1195858	journal	November 2010
The 3' Untranslated Region of Sindbis Virus Represses Deadenylation of Viral Transcripts in Mosquito and Mammalian Cells Garneau, N. L.; Sokoloski, K. J.; Opyrchal, M. Journal of Virology, Vol. 82, Issue 2 https://doi.org/10.1128/JVI.01205-07	journal	October 2007
Cytoplasmic Decay of Intergenic Transcripts in Saccharomyces cerevisiae Thompson, D. M.; Parker, R. Molecular and Cellular Biology, Vol. 27, Issue 1 https://doi.org/10.1128/MCB.01023-06	journal	October 2006
An mRNA Stability Complex Functions with Poly(A)-Binding Protein To Stabilize mRNA In Vitro Wang, Zuoren; Day, Nancy; Trifillis, Panayiota Molecular and Cellular Biology, Vol. 19, Issue 7 https://doi.org/10.1128/MCB.19.7.4552	journal	July 1999
Molecular mechanism for preQ ₁ -II riboswitch function revealed by molecular dynamics Aytenfisu, Asaminew H.; Liberman, Joseph A.; Wedekind, Joseph E. RNA, Vol. 21, Issue 11 https://doi.org/10.1261/rna.051367.115	journal	September 2015
Hoogsteen-position pyrimidines promote the stability and function of the MALAT1 RNA triple helix Brown, Jessica A.; Kinzig, Charles G.; DeGregorio, Suzanne J. RNA, Vol. 22, Issue 5 https://doi.org/10.1261/rna.055707.115	journal	March 2016
The Impact of a Ligand Binding on Strand Migration in the SAM-I Riboswitch Huang, Wei; Kim, Joohyun; Jha, Shantenu PLoS Computational Biology, Vol. 9, Issue 5 https://doi.org/10.1371/journal.pcbi.1003069	journal	May 2013
Characterizing Complex Dynamics in the Transactivation Response Element Apical Loop and Motional Correlations with the Bulge by NMR, Molecular Dynamics, and Mutagenesis Dethoff, Elizabeth A.; Hansen, Alexandar L.; Musselman, Catherine Biophysical Journal, Vol. 95, Issue 8 https://doi.org/10.1529/biophysj.108.140285	journal	October 2008

Similar Records

Structural analyses of an RNA stability element interacting with poly(A)

Journal Article · Sun Feb 21 19:00:00 EST 2021 · Proceedings of the National Academy of Sciences of the United States of America · OSTI ID:1798368

Identification and characterization of a class of MALAT1 -like genomic loci

Journal Article · Mon May 22 20:00:00 EDT 2017 · Cell Reports · OSTI ID:1364397

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
ENE
RNA dynamics
lncRNA
molecular dynamics
small angle X-ray scattering

A highly ordered, nonprotective MALAT1 ENE structure is adopted prior to triplex formation

Citation Formats

References (52)

Similar Records

Related Subjects