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Cited by 118HIV Research and TreatmentRNA and protein synthesis mechanismsRNA Research and Splicing

Structural basis for transcriptional start site control of HIV-1 RNA fate

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Brown, Joshua D., Kharytonchyk, Siarhei, Chaudry, Issac, Iyer, Aishwarya S., Carter, Hannah, Becker, Ghazal, Desai, Yash, Glang, Lindsay +15 more·2020·Science
DOI 10.1126/science.aaz7959PMC PMC7351118
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Abstract

One guanosine determines transcript fate Transcripts of the HIV-1 RNA genome can be either spliced and translated into viral proteins or packaged into new virions as a progeny genome. The path taken depends on whether the transcript contains one guanosine at the 5′ terminus (1G) rather than two or three (2G or 3G). Brown et al. used nuclear magnetic resonance spectroscopy to show that 1G transcripts adopt a dimeric structure that sequesters a terminal cap required for translation and splicing but exposes sites that bind to the HIV-1 Gag protein, which recruits the genome during viral assembly. Conversely, 2G or 3G transcripts have the cap accessible, but Gag-binding sites are sequestered. Therefore, a single guanosine acts as a conformational switch to determine the fate of HIV-1 transcripts. Science , this issue p. 413

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  • The 1 G RNA preferentially adopts conformations that leave the DIS and Gag-binding motifs such as unpaired purines fully exposed thus favoring gRNA packaging.

    “The 1 G RNA preferentially adopts conformations that leave the DIS and Gag-binding motifs such as unpaired purines fully exposed thus favoring gRNA packaging.”

    From Beyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication (2026) · cites this paper as Brown et al. 2020

    The passage labeled Abstract (page not provided) says single-guanine transcripts adopt a dimeric structure that exposes Gag-binding sites, and the copy identifies a DIS hairpin in the Cap1G leader. It also reports enrichment of Cap1G transcripts in virions. The passages do not establish that unpaired purines are fully exposed, so that specific description goes beyond the evidence shown. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • HIV-1 generates multiple unspliced RNA species (e.g. 1 G versus 3 G RNAs) that differ only slightly at the 5′ end, but fold into distinct structures with differing packaging efficiencies.

    “HIV-1 generates multiple unspliced RNA species (e.g. 1 G versus 3 G RNAs) that differ only slightly at the 5′ end, but fold into distinct structures with differing packaging efficiencies.”

    From Beyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication (2026) · cites this paper as Brown et al. 2020

  • The 3 G RNA adopts a different conformation in which DIS and Gag binding sites are obscured, rendering it more disposed to translation than to packaging.

    “On the other hand, the 3 G RNA adopts a different conformation in which DIS and Gag binding sites are obscured, rendering it more disposed to translation than to packaging”

    From Beyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication (2026) · cites this paper as Brown et al. 2020

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Research works printed but not linked: 48

  1. [1]Coffin JM, Hughes SH, Varmus HE, Retroviruses. (Cold Spring Harbor Laboratory Press, Plainview, N.Y., 1997). 21433340
  2. [3]Lu K, Heng X, Summers MF, Structural determinants and mechanism of HIV-1 genome packaging. J. Mol. Biol. 410, 609– 633 (2011). 21762803 PMC3139105
  3. [4]Kuzembayeva M, Dilley K, Sardo L, Hu W-S, Life of psi: how full-length HIV-1 RNAs become packaged genomes in the viral particles. Virology 454–455, 362– 370 (2014). PMC6258065 24530126
  4. [5]Onafuwa-Nuga A, Telesnitsky A, The remarkable frequency of human immunodeficiency virus type 1 genetic recombination. Microbiol Mol Biol Rev 73, 451– 480 (2009). 19721086 PMC2738136
  5. [7]Abbink TEM, Ooms M, Haasnoot PCJ, Berkhout B, The HIV-1 Leader RNA Conformational Switch Regulates RNA Dimerization but Does Not Regulate mRNA Translation†. Biochemistry 44, 9058– 9066 (2005). 15966729
  6. [8]Lu K, NMR detection of structures in the HIV-1 5’-leader RNA that regulate genome packaging. Science 344, 242– 245 (2011). PMC3335204 21998393
  7. [9]Darlix J-L, Gabus C, Nugeyre M-T, Clavel F, Barre-Sinoussi F, Cis elements and trans-acting factors involved in the RNA dimerization of the human immunodeficiency virus HIV-1. J. Mol. Biol. 216, 689– 699 (1990). 2124274
  8. [10]Ooms M, Huthoff H, Russell R, Liang C, Berkhout B, A riboswitch regulates RNA dimerization and packaging in human immunodeficiency virus type 1 virions. J. Virol. 78, 10814– 10819(2004). 15367648 PMC516375
  9. [11]Masuda T, Fate of HIV-1 cDNA intermediates during reverse transcription is dictated by transcription initiation site of virus genomic RNA. Sci Rep 5, 17680 (2015). 26631448 PMC4668388
  10. [12]Kharytonchyk S, Transcriptional start site heterogeneity modulates the structure and function of the HIV-1 genome. Proc Natl Acad Sci USA 113, 13378– 13383 2016). 27834211 PMC5127319
  11. [13]Chiu YL, Coronel E, Ho CK, Shuman S, Rana TM, HIV-1 Tat protein interacts with mammalian capping enzyme and stimulates capping of TAR RNA. J Biol Chem 276, 12959– 12966 (2001). 11278368
  12. [14]Zhou M, The Tat/TAR-dependent phosphorylation of RNA polymerase II Cterminal domain stimulates cotranscriptional capping of HIV-1 mRNA. Proc Natl Acad Sci USA 100, 12666– 12671 (2003). 14569024 PMC240675
  13. [15]Menees TM, Muller B, Krausslich HG, The major 5’ end of HIV type 1 RNA corresponds to G456. AIDS Res Hum Retroviruses 23, 1042– 1048 (2007). 17725422
  14. [16]Sharma A, Yilmaz A, Marsh K, Cochrane A, Boris-Lawrie K, Thriving under stress: selective translation of HIV-1 structural protein mRNA during Vpr-mediated impairment of eIF4E translation activity. PLoSPathog 8, el002612 (2012). PMC3310836 22457629
  15. [17]Ramanathan A, Robb GB, Chan SH, mRNA capping: biological functions and applications. Nucleic Acids Res 44, 7511– 7526 (2016). 27317694 PMC5027499
  16. [18]Alizon M, Wain-Hobson S, Gluckman J-C, Sonigo P, Genetic variability of the AIDS virus: nucleotide sequence analysis of two isolates from African patients. Cell, 63– 74 (1986). 2424612
  17. [19]Tran T, Conserved determinants of lentiviral genome dimerization. Retrovirolosy 12, 83 (2015). PMC4588261 26420212
  18. [20]Wüthrich K, NMR of Proteins and Nucleic Acids. (John Wiley & Sons, New York, 1986).
  19. [21]Heng X, Identification of a minimal region of the HIV-1 5’-leader required for RNA dimerization, NC binding, and packaging. JMolBiol 417, 224– 239 (2012). PMC3296369 22306406
  20. [22]Brown JD, Summers MF, Johnson BA, Prediction of hydrogen and carbon chemical shifts from RNA using database mining and support vector regression. Journal of biomolecular NMR 63, 39– 52 (2015). 26141454 PMC4669054
  21. [23]Abbink TEM, Berkhout B, A novel long distance base-pairing interaction in Human Immunodeficiency Virus Type 1 RNA occludes the Gag start codon. J. Biol. Chem. 278, 11601– 11611 (2003). 12458192
  22. [24]Xia et ah T, Thermodynamic parameters for an expanded nearest-neighbor model for formation of RNA duplexes with Watson-Crick base pairs. Biochemistry 37, 14719 14735 (1998). 9778347
  23. [25]Gingras AC, Raught B, Sonenberg N, eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annu Rev Biochem 68, 913– 963 (1999). 10872469
  24. [26]Wang Z, Jiao X, Carr-Schmid A, Kiledjian M, The hDcp2 protein is a mammalian mRNA decapping enzyme. Proc Natl Acad Sci USA 99, 12663– 12668 (2002). 12218187 PMC130517
  25. [27]Keane etal SC., Structure of the HIV-1 RNA packaging signal. Science 348, 917– 921 (2015). 25999508 PMC4492308
  26. [28]Serganov A, Nudler E, A decade of riboswitches. Cell 152, 17– 24 (2013). 23332744 PMC4215550
  27. [29]Lewis JD, Izaurralde E, The role of the cap structure in RNA processing and nuclear export. Eur J Biochem 247, 461– 469 (1997). 9266685
  28. [31]Boeras I, The basal translation rate of authentic HIV-1 RNA is regulated by 5’UTR nt-pairings at junction of R and U5. Sci Rep 7, 6902 (2017). 28761163 PMC5537239
  29. [33]Frith MC, A code for transcription initiation in mammalian genomes. Genome Res 18, 1– 12 (2008). 18032727 PMC2134772
  30. [34]De la Pena M, Kyrieleis OJ, Cusack S, Structural insights into the mechanism and evolution of the vaccinia virus mRNA cap N7 methyl-transferase. EMBO J 26, 4913 4925 (2007). 17989694 PMC2099473
  31. [36]Thompson JD, Higgins DG, Gibson TJ, CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 22, 4673– 4680 (1994). 7984417 PMC308517
  32. [37]Waterhouse AM, Procter JB, Martin DM, Clamp M, Barton GJ, Jalview Version 2—a multiple sequence alignment editor and analysis workbench. Bioinformatics 25, 1189– 1191 (2009). 19151095 PMC2672624
  33. [38]Norris M, Fetler B, Marchant J, Johnson BA, NMRFx Processor: a cross-platform NMR data processing program. Journal of biomolecular NMR, 1– 12 (2016). PMC4983292 27457481
  34. [39]Johnson BA, Blevins RA, NMRview: a Computer Program for the Visualization and Analysis of NMR Data. J. Biomol. NMR 4, 603– 614 (1994). 22911360
  35. [40]Barton S, Heng X, Johnson BA, Summers MF, Database proton NMR chemical shifts for RNA signal assignment and validation. Journal of biomolecular NMR 55, 33– 46 (2013). 23180050 PMC3555346
  36. [41]Marchant J, Summers MF, Johnson BA, Assigning NMR spectra of RNA, peptides and small organic molecules using molecular network visualization software. Journal of biomolecular NMR 73, 525– 529 (2019). 31325088 PMC6859155
  37. [42]Tolbert BS, Major groove width variations in RNA structures determined by NMR and impact of 13C residual chemical shift anisotropy and 1H-13C residual dipolar coupling on refinement. J. Biomol. NMR 47, 205– 219 (2010). 20549304 PMC2929647
  38. [43]Case DA, The Amber biomolecular simulation programs. J. Computat. Chem. 26, 1668– 1688 (2005). PMC1989667 16200636
  39. [44]Yildirim I, Stern HA, Tubbs JD, Kennedy SD, Turner DH, Benchmarking AMBER force fields for RNA: comparisons to NMR spectra for single-stranded r(GACC) are improved by revised chi torsions. J Phys Chem B 115, 9261– 9270 (2011). 21721539 PMC3140773
  40. [45]Zgarbova M, Refinement of the Cornell et al. Nucleic Acids Force Field Based on Reference Quantum Chemical Calculations of Glycosidic Torsion Profiles. J Chem Theory Comput 7, 2886– 2902 (2011). 21921995 PMC3171997
  41. [46]Mongan J, Simmerling C, McCammon JA, Case DA, Onufriev A, Generalized born model with a simple, robust molecular volume correction. J. Chem. Theory Comput. 3, 156– 169(2007). 21072141 PMC2975579
  42. [47]Aduri R, AMBER Force Field Parameters for the Naturally Occurring Modified Nucleosides in RNA. J Chem Theory Comput 3, 1464– 1475 (2007). 26633217
  43. [48]Meagher KL, Redman LT, Carlson HA, Development of polyphosphate parameters for use with the AMBER force field. J Comput Chem 24, 1016– 1025 (2003). 12759902
  44. [50]Zuker M, Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res 31, 3406– 3415 (2003). 12824337 PMC169194
  45. [51]Reuter JS, Mathews DH, RNAstructure: software for RNA secondary structure prediction and analysis. BMC bioinformatics 11, 129 (2010). 20230624 PMC2984261
  46. [52]Marquet R, Paillart J-C, Skripkin E, Ehresmann C, Ehresmann B, Dimerization of human immunodeficiency virus type 1 RNA involves sequences located upstream of the splice donor site. Nucl. Acids Res. 22, 145– 151 (1994). 8121797 PMC307764
  47. [53]Davis IW, MolProbity: all-atom contacts and structure validation for proteins and nucleic acids. Nucleic Acids Res 35, W375– 383 (2007). 17452350 PMC1933162
  48. [54]Chen VB, MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr D Biol Crystallogr 66, 12– 21 (2010). 20057044 PMC2803126

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Authors
Brown, J. D., Kharytonchyk, S., Chaudry, I., Iyer, A. S., Carter, H., Becker, G., Desai, Y., Glang, L., Choi, S. H., Singh, K., Lopresti, M. W., Orellana, M., Rodriguez, T., Oboh, U., Hijji, J., Ghinger, F. G., Stewart, K., Francis, D., Edwards, B., Chen, P., Case, D. A., Telesnitsky, A., & Summers, M. F.
Affiliations
  • Howard Hughes Medical Institute (US)
  • University of Michigan (US)
  • Rutgers, The State University of New Jersey (US)
Corresponding author
  • Telesnitsky, Alice
  • Summers, Michael F.
ORCID
Venue
Science
Publisher
American Association for the Advancement of Science (AAAS)
Published
2020-04-24
Volume
368
Issue
6489
Pages
413-417
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
DOI
10.1126/science.aaz7959
PMC
PMC7351118
OpenAlex
W3020490292
Cited by
118
References
4
Citations by year
2026: 14 · 2025: 15 · 2024: 20 · 2023: 14 · 2022: 18 · 2021: 26 · 2020: 11
FWCI
9.09
Type
journal article
Language
en
Open access
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Rutgers University Community Repository (Rutgers University) (submittedVersion)
Funders
NIH Office of the Director (AI50498, AI150470, GM123803)
Topics
  • Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
Keywords
HIV-1, transcription start sites, RNA dimerization, viral RNA packaging, viral assembly, translation initiation, splicing
MeSH terms
Base Composition, Guanosine, Humans, RNA Caps, RNA, Messenger, RNA, Viral, Protein Biosynthesis, HIV-1, Gene Expression Regulation, Viral, Nuclear Magnetic Resonance, Biomolecular, Base Pairing, 5' Untranslated Regions, Transcription Initiation Site, Eukaryotic Initiation Factor-4E

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