Hachimoji DNA and RNA: A genetic system with eight building blocks.
Open accessAbstract
We report DNA- and RNA-like systems built from eight nucleotide "letters" (hence the name "hachimoji") that form four orthogonal pairs. These synthetic systems meet the structural requirements needed to support Darwinian evolution, including a polyelectrolyte backbone, predictable thermodynamic stability, and stereoregular building blocks that fit a Schrödinger aperiodic crystal. Measured thermodynamic parameters predict the stability of hachimoji duplexes, allowing hachimoji DNA to increase the information density of natural terran DNA. Three crystal structures show that the synthetic building blocks do not perturb the aperiodic crystal seen in the DNA double helix. Hachimoji DNA was then transcribed to give hachimoji RNA in the form of a functioning fluorescent hachimoji aptamer. These results expand the scope of molecular structures that might support life, including life throughout the cosmos.
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Four new synthetic nucleic acids-6-Amino-5-nitropyridin-2-one (Z), 5-Aza-7-deazaguanine (P), Isocytosine (S), and Isoguanine (B)-are reported.
“Finally, four new synthetic nucleic acids: 6-Amino-5-nitropyridin-2-one (Z), 5-Aza-7-deazaguanine (P), Isocytosine (S), and Isoguanine (B) are reported (Hoshika et al., 2019).”
From Large-Scale de Novo Oligonucleotide Synthesis for Whole-Genome Synthesis and Data Storage: Challenges and Opportunities (2021) · cites this paper as Hoshika et al., 2019
As alternative chemistries emerge, including unnatural nucleotides and small molecules that can modulate the structure of DNA, the parameter space for structure- and sequence-based DNA data storage is continually expanding.
“Additionally, as alternative chemistries emerge, including unnatural nucleotides147 and small molecules that can modulate the structure of DNA,148 the parameter space for structure- and sequence-based DNA data storage is continually expanding.”
From Emerging Approaches to DNA Data Storage: Challenges and Prospects (2022) · cites this paper as [147]
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Features and development of Coot
Emsley, P., Lohkamp, B., Scott, W. G., & Cowtan, K. D. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444910007493 · Cited by 27,510 · see citing works
<i>PHENIX</i> : a comprehensive Python-based system for macromolecular structure solution
Adams, P. D., Afonine, P. V., Bunkóczi, G., Chen, V. B., Davis, I. W., Echols, N., Headd, J. J., Hung, L.-W., Kapral, G. J., Grosse-Kunstleve, R. W., et al. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444909052925 · Cited by 23,716 · see citing works
<i>Phaser</i> crystallographic software
McCoy, A. J., Grosse-Kunstleve, R. W., Adams, P. D., Winn, M. D., Storoni, L. C., & Read, R. J. (2007) · Journal of Applied Crystallography · doi:10.1107/s0021889807021206 · Cited by 20,612 · see citing works
Kabsch, W. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444909047337 · Cited by 16,463 · see citing works
Refinement of Macromolecular Structures by the Maximum-Likelihood Method
Murshudov, G. N., Vagin, A. A., & Dodson, E. J. (1997) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444996012255 · Cited by 14,671 · see citing works
Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid
WATSON, J. D., & CRICK, F. H. C. (1953) · Nature · doi:10.1038/171737a0 · Cited by 13,584 · see citing works
How good are my data and what is the resolution?
Evans, P. R., & Murshudov, G. N. (2013) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444913000061 · Cited by 4,747 · see citing works
A unified view of polymer, dumbbell, and oligonucleotide DNA nearest-neighbor thermodynamics.
SantaLucia, J. (1998) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.95.4.1460 · Cited by 2,791 · see citing works
Self-citationLu, X. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkg680 · Cited by 1,669 · see citing works
RNA Mimics of Green Fluorescent Protein
Paige, J. S., Wu, K., & Jaffrey, S. R. (2011) · Science · doi:10.1126/science.1207339 · Cited by 1,353 · see citing works
Thermodynamics and NMR of Internal G·T Mismatches in DNA
Allawi, H. T., & SantaLucia, J. (1997) · Biochemistry · doi:10.1021/bi962590c · Cited by 623 · see citing works
Self-citationGeneration of high-affinity DNA aptamers using an expanded genetic alphabet
Kimoto, M., Yamashige, R., Matsunaga, K., Yokoyama, S., & Hirao, I. (2013) · Nature Biotechnology · doi:10.1038/nbt.2556 · Cited by 511 · see citing works
Model bias in macromolecular crystal structures
Hodel, A. E., Kim, S., & Brünger, A. T. (1992) · Acta Crystallographica Section A Foundations of Crystallography · doi:10.1107/s0108767392006044 · Cited by 405 · see citing works
A semi-synthetic organism that stores and retrieves increased genetic information
Zhang, Y., Ptacin, J. L., Fischer, E. C., Aerni, H. R., Caffaro, C. E., Jose, K. M. S., Feldman, A. W., Turner, C. R., & Romesberg, F. E. (2017) · Nature · doi:10.1038/nature24659 · Cited by 354 · see citing works
A G-quadruplex–containing RNA activates fluorescence in a GFP-like fluorophore
Huang, H., Suslov, N. B., Li, N., Shelke, S. A., Evans, M., Koldobskaya, Y., Rice, P. A., & Piccirilli, J. A. (2014) · Nature Chemical Biology · doi:10.1038/nchembio.1561 · Cited by 349 · see citing works
Self-citationMoran, S. D., Ren, R. X.-F., Rumney, & Kool, E. T. (1997) · Journal of the American Chemical Society · doi:10.1021/ja963718g · Cited by 318 · see citing works
Amplification, Mutation, and Sequencing of a Six-Letter Synthetic Genetic System
Yang, Z., Chen, F., Alvarado, J. B., & Benner, S. A. (2011) · Journal of the American Chemical Society · doi:10.1021/ja204910n · Cited by 302 · see citing works
Self-citationMcDowell, J. A., & Turner, D. H. (1996) · Biochemistry · doi:10.1021/bi9615710 · Cited by 297 · see citing works
An unnatural base pair for incorporating amino acid analogs into proteins
Hirao, I., Ohtsuki, T., Fujiwara, T., Mitsui, T., Yokogawa, T., Okuni, T., Nakayama, H., Takio, K., Yabuki, T., Kigawa, T., et al. (2002) · Nature Biotechnology · doi:10.1038/nbt0202-177 · Cited by 283 · see citing works
Bain, J. D., Switzer, C., Chamberlin, R., & Benner, S. A. (1992) · Nature · doi:10.1038/356537a0 · Cited by 280 · see citing works
Self-citationEnzymic recognition of the base pair between isocytidine and isoguanosine
Switzer, C. Y., Moroney, S. E., & Benner, S. A. (1993) · Biochemistry · doi:10.1021/bi00090a027 · Cited by 253 · see citing works
Self-citationEvolution of Functional Six-Nucleotide DNA
Zhang, L., Yang, Z., Sefah, K., Bradley, K. M., Hoshika, S., Kim, M., Kim, H., Zhu, G., Jiménez, E., Cansız, S., et al. (2015) · Journal of the American Chemical Society · doi:10.1021/jacs.5b02251 · Cited by 238 · see citing works
Self-citationYang, Z., Hutter, D., Sheng, P., Sismour, A. M., & Benner, S. A. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkl633 · Cited by 196 · see citing works
Self-citationEnzymatic incorporation of a third nucleobase pair
Yang, Z., Sismour, A. M., Sheng, P., Puskar, N., & Benner, S. A. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm395 · Cited by 180 · see citing works
Self-citationKlenTaq polymerase replicates unnatural base pairs by inducing a Watson-Crick geometry
Betz, K., Malyshev, D. A., Lavergne, T., et al. (2012) · Nature Chemical Biology · doi:10.1038/nchembio.966 · Cited by 152 · see citing works
Spectrophotometry and spectrofluorimetry : a practical approach
Bashford, C. L., & Harris, D. A. (1987) · IRL Press eBooks · Cited by 146 · see citing works
Alternative Watson–Crick Synthetic Genetic SystemsPreprint
Benner, S. A., Karalkar, N. B., Hoshika, S., Laos, R., Shaw, R. W., Matsuura, M. F., Fajardo, D. A., & Moussatche, P. (2016) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a023770 · Cited by 99 · see citing works
Self-citationSismour, A. M. (2004) · Nucleic Acids Research · doi:10.1093/nar/gkh241 · Cited by 96 · see citing works
Meyer, A., Garry, D., Hall, B., Byrom, M., McDonald, H. G., Yang, X., Yin, Y., & Ellington, A. D. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv734 · Cited by 76 · see citing works
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DasGupta, S., Shelke, S. A., Li, N., et al. (2015) · Chemical Communications · doi:10.1039/c5cc01526j · Cited by 72 · see citing works
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Leal, N. A., Kim, H., Hoshika, S., Kim, M., Carrigan, M. A., & Benner, S. A. (2014) · ACS Synthetic Biology · doi:10.1021/sb500268n · Cited by 57 · see citing works
Self-citationWieser, W. (1995) · Merkur · Cited by 51 · see citing works
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Kim, H., Leal, N. A., Hoshika, S., & Benner, S. A. (2014) · The Journal of Organic Chemistry · doi:10.1021/jo402665d · Cited by 32 · see citing works
Self-citationCoté, M. L., Yohannan, S., & Georgiadis, M. M. (2000) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444900008246 · Cited by 30 · see citing works
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Kim, H., Leal, N. A., & Benner, S. A. (2009) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2009.03.047 · Cited by 28 · see citing works
Self-citationSun, D., Jessen, S. M., Liu, C., Liu, X., Najmudin, S., & Georgiadis, M. M. (1998) · Protein Science · doi:10.1002/pro.5560070711 · Cited by 28 · see citing works
Self-citationSnapshots of an evolved DNA polymerase pre- and post-incorporation of an unnatural nucleotide
Singh, I., Laos, R., Hoshika, S., Benner, S. A., & Georgiadis, M. M. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky552 · Cited by 26 · see citing works
Self-citationOn the wagon—DNA polymerase joins "H-bonds anonymous"
Goodman, M. F. (1999) · Nature Biotechnology · doi:10.1038/10852 · Cited by 17 · see citing works
Montaño, S. P., Coté, M. L., Roth, M. J., & Georgiadis, M. M. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkl693 · Cited by 15 · see citing works
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- Authors
- Hoshika, S., Leal, N. A., Kim, M.-J., Kim, M.-S., Karalkar, N. B., Kim, H.-J., Bates, A. M., Watkins, N. E., SantaLucia, H. A., Meyer, A. J., DasGupta, S., Piccirilli, J. A., Ellington, A. D., SantaLucia, J., Georgiadis, M. M., & Benner, S. A.
- Affiliations
- Firebird Biomolecular Sciences (United States) (US)
- Indiana University School of Medicine (US)
- DNA Software (United States) (US)
- The University of Texas at Austin (US)
- University of Chicago (US)
- Corresponding author
- Hoshika, Shuichi
- Leal, Nicole A.
- Benner, Steven A.
- ORCID
- Venue
- Science
- Published
- 2019-02-22
- Volume
- 363
- Issue
- 6429
- Pages
- 884-887
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC6413494
- OpenAlex
- W2917003832
- Cited by
- 494
- References
- 39
- Citations by year
- 2026: 32 · 2025: 36 · 2024: 54 · 2023: 74 · 2022: 84 · 2021: 93 · 2020: 70 · 2019: 51
- FWCI
- 24.66
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- PMC
- Funders
- National Institutes of Health (R41GM119494, R01GM128186, P41GM103393, 5 R01 GM102489-07)
- U.S. Department of Energy (DE-AC02-76SF00515)
- National Aeronautics and Space Administration (NNX15AF46G)
- Defense Threat Reduction Agency (HDTRA1-13-1-0004)
- John Templeton Foundation (54466)
- Templeton World Charity Foundation, Inc. (0092/AB57)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Physical Sciences › Physics and Astronomy › Astronomy and Astrophysics › Origins and Evolution of Life
- Keywords
- synthetic nucleotides, information density, transcription, fluorescent aptamers, origin of life, extraterrestrial life
- MeSH terms
- Polyelectrolytes, Crystallography, DNA, Fluorescence, Nucleic Acid Conformation, Nucleotides, RNA, Thermodynamics, Base Pairing, Synthetic Biology
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