Xeno nucleic acid

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Glycol nucleic acid (left) is an example of a xeno nucleic acid because it has a different backbone than DNA (right). GNA-T vs. natural DNA-T.png
Glycol nucleic acid (left) is an example of a xeno nucleic acid because it has a different backbone than DNA (right).

Xeno nucleic acids (XNA) are synthetic nucleic acid analogues that have a different backbone from the ribose and deoxyribose found in the nucleic acids of naturally occurring RNA and DNA. [1]

Contents

The same nucleobases can be used to store genetic information and interact with DNA, RNA, or other XNA bases, but the different backbone gives the structure different stability, and it cannot be processed by naturally occurring cellular processes. For example, natural DNA polymerases cannot read and duplicate this information, thus the genetic information stored in XNA is invisible to DNA-based organisms. [2]

As of 2011, at least six types of synthetic sugars have been shown to form nucleic acid backbones that can store and retrieve genetic information. Research is now being done to create synthetic polymerases to transform XNA. The study of its production and application has created a field known as xenobiology.[ citation needed ]

Background

The structure of DNA was discovered in 1953. Around the early 2000s, researchers created a number of exotic DNA-like structures, XNA. These are synthetic polymers that can carry the same information as DNA, but with different molecular constituents. The "X" in XNA stands for "xeno-", meaning strange or alien, indicating the difference in the molecular structure as compared to DNA or RNA. [3]

Not much was done with XNA until the development of special polymerase enzyme, capable of copying XNA from a DNA template as well as copying XNA back into DNA. [3] Pinheiro et al. (2012), for example, has demonstrated such an XNA-capable polymerase that works on sequences of around 100 base pairs in length. [4] More recently, synthetic biologists Philipp Holliger and Alexander Taylor succeeded in creating XNAzymes, the XNA equivalent of a ribozyme, enzymes made of RNA. This demonstrates that XNAs not only store hereditary information, but can also serve as enzymes, raising the possibility that life elsewhere could have begun with something other than RNA or DNA. [5]

Structure

Strands of DNA and RNA are formed by stringing together long chains of molecules called nucleotides. A nucleotide is made up of three chemical components: a phosphate, a five-carbon sugar group (this can be either a deoxyribose sugar—which gives us the "D" in DNA—or a ribose sugar—the "R" in RNA), and one of five standard bases (adenine, guanine, cytosine, thymine or uracil).

The molecules that piece together to form the xeno nucleic acids are almost identical to those of DNA and RNA, with one exception: in XNA nucleotides, the deoxyribose and ribose sugar groups of DNA and RNA have been replaced with other chemical structures. These substitutions make XNAs functionally and structurally analogous to DNA and RNA despite being unnatural and artificial.

XNA exhibits a variety of structural chemical changes relative to its natural counterparts. Types of synthetic XNA created so far include: [2]

HNA could potentially be used as a drug that can recognize and bind to specified sequences. Scientists have been able to isolate HNAs for the possible binding of sequences that target HIV. [6] Research has also shown that CeNAs with stereochemistry similar to the D form[ clarification needed ][ dextro form of what? ] can create stable duplexes with itself and RNA. It was shown that CeNAs are not as stable when they form duplexes with DNA. [7]

Implications

The study of XNA is not intended to give scientists a better understanding of biological evolution as it has occurred historically, but rather to explore ways in which we might control and even reprogram the genetic makeup of biological organisms in future. XNA has shown significant potential in solving the current issue of genetic pollution in genetically modified organisms. [8] While DNA is incredibly efficient in its ability to store genetic information and lend complex biological diversity, its four-letter genetic alphabet is relatively limited. Using a genetic code of six XNAs rather than the four naturally occurring DNA nucleotide bases yields endless opportunities for genetic modification and expansion of chemical functionality. [9]

The development of various hypotheses and theories about XNAs have altered a key factor in our current understanding of nucleic acids: heredity and evolution are not limited to DNA and RNA as once thought, but are simply processes that have developed from polymers capable of storing information. [4] Investigations into XNAs will allow researchers to assess whether DNA and RNA are the most efficient and desirable building blocks of life, or if these two molecules emerged randomly after evolving from a larger class of chemical ancestors. [10]

Applications

One theory of XNA utilization is its incorporation into medicine as a disease-fighting agent. Some enzymes and antibodies that are currently administered for various disease treatments are broken down too quickly in the stomach or bloodstream. Because XNA is foreign and because it is believed that humans have not yet evolved the enzymes to break them down, XNAs may be able to serve as a more durable counterpart to the DNA and RNA-based treatment methodologies that are currently in use. [11]

Experiments with XNA have already allowed for the replacement and enlargement of this genetic alphabet, and XNAs have shown complementarity with DNA and RNA nucleotides, suggesting potential for its transcription and recombination. One experiment conducted at the University of Florida led to the production of an XNA aptamer by the AEGIS-SELEX (artificially expanded genetic information system - systematic evolution of ligands by exponential enrichment) method, followed by successful binding to a line of breast cancer cells. [12] Furthermore, experiments in the model bacterium E. coli have demonstrated the ability for XNA to serve as a biological template for DNA in vivo. [13]

In moving forward with genetic research on XNAs, various questions must come into consideration regarding biosafety, biosecurity, ethics, and governance/regulation. [2] One of the key questions here is whether XNA in an in vivo setting would intermix with DNA and RNA in its natural environment, thereby rendering scientists unable to control or predict its implications in genetic mutation. [11]

XNA also has potential applications to be used as catalysts, much like RNA has the ability to be used as an enzyme. Researchers have shown XNA is able to cleave and ligate DNA, RNA and other XNA sequences, with the most activity being XNA catalyzed reactions on XNA molecules. This research may be used in determining whether DNA and RNA's role in life emerged through natural selection processes or if it was simply a coincidental occurrence. [14]

XNA may be employed as molecular clamps in quantitative real-time polymerase chain reactions (qPCR) by hybridizing with target DNA sequences. [15] In a study published in PLOS ONE, an XNA-mediated molecular clamping assay detected mutant cell-free DNA (cfDNA) from precancerous colorectal cancer (CRC) lesions and colorectal cancer. [15] XNA may also act as highly specific molecular probes for detection of nucleic acid target sequence. [16]

Related Research Articles

<span class="mw-page-title-main">DNA</span> Molecule that carries genetic information

Deoxyribonucleic acid is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of all known organisms and many viruses. DNA and ribonucleic acid (RNA) are nucleic acids. Alongside proteins, lipids and complex carbohydrates (polysaccharides), nucleic acids are one of the four major types of macromolecules that are essential for all known forms of life.

<span class="mw-page-title-main">Nucleic acid</span> Class of large biomolecules essential to all known life

Nucleic acids are large biomolecules that are crucial in all cells and viruses. They are composed of nucleotides, which are the monomer components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main classes of nucleic acids are deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). If the sugar is ribose, the polymer is RNA; if the sugar is deoxyribose, a variant of ribose, the polymer is DNA.

<span class="mw-page-title-main">Nucleotide</span> Biological molecules constituting nucleic acids

Nucleotides are organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules within all life-forms on Earth. Nucleotides are obtained in the diet and are also synthesized from common nutrients by the liver.

<span class="mw-page-title-main">RNA</span> Family of large biological molecules

Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself or by forming a template for the production of proteins. RNA and deoxyribonucleic acid (DNA) are nucleic acids. The nucleic acids constitute one of the four major macromolecules essential for all known forms of life. RNA is assembled as a chain of nucleotides. Cellular organisms use messenger RNA (mRNA) to convey genetic information that directs synthesis of specific proteins. Many viruses encode their genetic information using an RNA genome.

<span class="mw-page-title-main">RNA world</span> Hypothetical stage in the early evolutionary history of life on Earth

The RNA world is a hypothetical stage in the evolutionary history of life on Earth, in which self-replicating RNA molecules proliferated before the evolution of DNA and proteins. The term also refers to the hypothesis that posits the existence of this stage.

<span class="mw-page-title-main">Nucleobase</span> Nitrogen-containing biological compounds that form nucleosides

Nucleobases are nitrogen-containing biological compounds that form nucleosides, which, in turn, are components of nucleotides, with all of these monomers constituting the basic building blocks of nucleic acids. The ability of nucleobases to form base pairs and to stack one upon another leads directly to long-chain helical structures such as ribonucleic acid (RNA) and deoxyribonucleic acid (DNA). Five nucleobases—adenine (A), cytosine (C), guanine (G), thymine (T), and uracil (U)—are called primary or canonical. They function as the fundamental units of the genetic code, with the bases A, G, C, and T being found in DNA while A, G, C, and U are found in RNA. Thymine and uracil are distinguished by merely the presence or absence of a methyl group on the fifth carbon (C5) of these heterocyclic six-membered rings. In addition, some viruses have aminoadenine (Z) instead of adenine. It differs in having an extra amine group, creating a more stable bond to thymine.

<span class="mw-page-title-main">Nucleoside</span> Any of several glycosylamines comprising a nucleobase and a sugar molecule

Nucleosides are glycosylamines that can be thought of as nucleotides without a phosphate group. A nucleoside consists simply of a nucleobase and a five-carbon sugar whereas a nucleotide is composed of a nucleobase, a five-carbon sugar, and one or more phosphate groups. In a nucleoside, the anomeric carbon is linked through a glycosidic bond to the N9 of a purine or the N1 of a pyrimidine. Nucleotides are the molecular building blocks of DNA and RNA.

<span class="mw-page-title-main">Ribozyme</span> Type of RNA molecules

Ribozymes are RNA molecules that have the ability to catalyze specific biochemical reactions, including RNA splicing in gene expression, similar to the action of protein enzymes. The 1982 discovery of ribozymes demonstrated that RNA can be both genetic material and a biological catalyst, and contributed to the RNA world hypothesis, which suggests that RNA may have been important in the evolution of prebiotic self-replicating systems.

<span class="mw-page-title-main">DNA synthesis</span>

DNA synthesis is the natural or artificial creation of deoxyribonucleic acid (DNA) molecules. DNA is a macromolecule made up of nucleotide units, which are linked by covalent bonds and hydrogen bonds, in a repeating structure. DNA synthesis occurs when these nucleotide units are joined to form DNA; this can occur artificially or naturally. Nucleotide units are made up of a nitrogenous base, pentose sugar (deoxyribose) and phosphate group. Each unit is joined when a covalent bond forms between its phosphate group and the pentose sugar of the next nucleotide, forming a sugar-phosphate backbone. DNA is a complementary, double stranded structure as specific base pairing occurs naturally when hydrogen bonds form between the nucleotide bases.

<span class="mw-page-title-main">Phosphodiester bond</span> –O– linkage between phosphoric acid and two other compounds

In chemistry, a phosphodiester bond occurs when exactly two of the hydroxyl groups in phosphoric acid react with hydroxyl groups on other molecules to form two ester bonds. The "bond" involves this linkage C−O−PO−2O−C. Discussion of phosphodiesters is dominated by their prevalence in DNA and RNA, but phosphodiesters occur in other biomolecules, e.g. acyl carrier proteins, phospholipids and the cyclic forms of GMP and AMP.

<span class="mw-page-title-main">Ribonucleotide</span> Nucleotide containing ribose as its pentose component

In biochemistry, a ribonucleotide is a nucleotide containing ribose as its pentose component. It is considered a molecular precursor of nucleic acids. Nucleotides are the basic building blocks of DNA and RNA. Ribonucleotides themselves are basic monomeric building blocks for RNA. Deoxyribonucleotides, formed by reducing ribonucleotides with the enzyme ribonucleotide reductase (RNR), are essential building blocks for DNA. There are several differences between DNA deoxyribonucleotides and RNA ribonucleotides. Successive nucleotides are linked together via phosphodiester bonds.

Xenobiology (XB) is a subfield of synthetic biology, the study of synthesizing and manipulating biological devices and systems. The name "xenobiology" derives from the Greek word xenos, which means "stranger, alien". Xenobiology is a form of biology that is not (yet) familiar to science and is not found in nature. In practice, it describes novel biological systems and biochemistries that differ from the canonical DNA–RNA-20 amino acid system. For example, instead of DNA or RNA, XB explores nucleic acid analogues, termed xeno nucleic acid (XNA) as information carriers. It also focuses on an expanded genetic code and the incorporation of non-proteinogenic amino acids, or “xeno amino acids” into proteins.

<span class="mw-page-title-main">Phoebus Levene</span> American biochemist (1869–1940)

Phoebus Aaron Theodore Levene was a Russian-born American biochemist who studied the structure and function of nucleic acids. He characterized the different forms of nucleic acid, DNA from RNA, and found that DNA contained adenine, guanine, thymine, cytosine, deoxyribose, and a phosphate group.

Threose nucleic acid (TNA) is an artificial genetic polymer in which the natural five-carbon ribose sugar found in RNA has been replaced by an unnatural four-carbon threose sugar. Invented by Albert Eschenmoser as part of his quest to explore the chemical etiology of RNA, TNA has become an important synthetic genetic polymer (XNA) due to its ability to efficiently base pair with complementary sequences of DNA and RNA. The main difference between TNA and DNA/RNA is their backbones. DNA and RNA have their phosphate backbones attached to the 5' carbon of the deoxyribose or ribose sugar ring, respectively. TNA, on the other hand, has it's phosphate backbone directly attached to the 3' carbon in the ring, since it does not have a 5' carbon. This modified backbone makes TNA, unlike DNA and RNA, completely refractory to nuclease digestion, making it a promising nucleic acid analog for therapeutic and diagnostic applications.

<span class="mw-page-title-main">Nucleic acid metabolism</span> Process

Nucleic acid metabolism is a collective term that refers to the variety of chemical reactions by which nucleic acids are either synthesized or degraded. Nucleic acids are polymers made up of a variety of monomers called nucleotides. Nucleotide synthesis is an anabolic mechanism generally involving the chemical reaction of phosphate, pentose sugar, and a nitrogenous base. Degradation of nucleic acids is a catabolic reaction and the resulting parts of the nucleotides or nucleobases can be salvaged to recreate new nucleotides. Both synthesis and degradation reactions require multiple enzymes to facilitate the event. Defects or deficiencies in these enzymes can lead to a variety of diseases.

<span class="mw-page-title-main">Nucleic acid analogue</span> Compound analogous to naturally occurring RNA and DNA

Nucleic acid analogues are compounds which are analogous to naturally occurring RNA and DNA, used in medicine and in molecular biology research. Nucleic acids are chains of nucleotides, which are composed of three parts: a phosphate backbone, a pentose sugar, either ribose or deoxyribose, and one of four nucleobases. An analogue may have any of these altered. Typically the analogue nucleobases confer, among other things, different base pairing and base stacking properties. Examples include universal bases, which can pair with all four canonical bases, and phosphate-sugar backbone analogues such as PNA, which affect the properties of the chain . Nucleic acid analogues are also called xeno nucleic acids and represent one of the main pillars of xenobiology, the design of new-to-nature forms of life based on alternative biochemistries.

Numerous key discoveries in biology have emerged from studies of RNA, including seminal work in the fields of biochemistry, genetics, microbiology, molecular biology, molecular evolution, and structural biology. As of 2010, 30 scientists have been awarded Nobel Prizes for experimental work that includes studies of RNA. Specific discoveries of high biological significance are discussed in this article.

<span class="mw-page-title-main">Hachimoji DNA</span> Synthetic DNA

Hachimoji DNA is a synthetic nucleic acid analog that uses four synthetic nucleotides in addition to the four present in the natural nucleic acids, DNA and RNA. This leads to four allowed base pairs: two unnatural base pairs formed by the synthetic nucleobases in addition to the two normal pairs. Hachimoji bases have been demonstrated in both DNA and RNA analogs, using deoxyribose and ribose respectively as the backbone sugar.

<span class="mw-page-title-main">Philipp Holliger</span> Swiss molecular biologist

Philipp Holliger is a Swiss molecular biologist best known for his work on xeno nucleic acids (XNAs) and RNA engineering. Holliger is a program leader at the MRC Laboratory of Molecular Biology.

This glossary of cellular and molecular biology is a list of definitions of terms and concepts commonly used in the study of cell biology, molecular biology, and related disciplines, including genetics, biochemistry, and microbiology. It is split across two articles:

References

  1. ↑ Schmidt M (2012). Synthetic Biology. John Wiley & Sons. pp. 151–. ISBN   978-3-527-65926-5 . Retrieved 9 May 2013.
  2. 1 2 3 Schmidt M (April 2010). "Xenobiology: a new form of life as the ultimate biosafety tool". BioEssays. 32 (4): 322–331. doi:10.1002/bies.200900147. PMC   2909387 . PMID   20217844.
  3. 1 2 Gonzales R (19 April 2012). "XNA Is Synthetic DNA That's Stronger than the Real Thing". Io9 . Retrieved 15 October 2015.
  4. 1 2 Pinheiro VB, Taylor AI, Cozens C, Abramov M, Renders M, Zhang S, et al. (April 2012). "Synthetic genetic polymers capable of heredity and evolution". Science. 336 (6079): 341–344. Bibcode:2012Sci...336..341P. doi:10.1126/science.1217622. PMC   3362463 . PMID   22517858.
  5. ↑ "World's first artificial enzymes created using synthetic biology". Medical Research Council . 1 December 2014. Archived from the original on 3 January 2018.
  6. ↑ Extance A (19 April 2012). "Polymers perform non-DNA evolution". Royal Society of Chemistry . Retrieved 15 October 2015.
  7. ↑ Gu P, Schepers G, Rozenski J, Van Aerschot A, Herdewijn P (2003). "Base pairing properties of D- and L-cyclohexene nucleic acids (CeNA)". Oligonucleotides. 13 (6): 479–489. doi:10.1089/154545703322860799. PMID   15025914.
  8. ↑ Herdewijn P, Marlière P (June 2009). "Toward safe genetically modified organisms through the chemical diversification of nucleic acids". Chemistry & Biodiversity. 6 (6): 791–808. doi:10.1002/cbdv.200900083. PMID   19554563. S2CID   8572188.
  9. ↑ Pinheiro VB, Holliger P (August 2012). "The XNA world: progress towards replication and evolution of synthetic genetic polymers". Current Opinion in Chemical Biology. 16 (3–4): 245–252. doi:10.1016/j.cbpa.2012.05.198. PMID   22704981.
  10. ↑ Hunter P (May 2013). "XNA marks the spot. What can we learn about the origins of life and the treatment of disease through artificial nucleic acids?". EMBO Reports. 14 (5): 410–413. doi:10.1038/embor.2013.42. PMC   3642382 . PMID   23579343.
  11. 1 2 "XNA: Synthetic DNA That Can Evolve". Popular Mechanics . 19 April 2012. Retrieved 17 November 2015.
  12. ↑ Sefah K, Yang Z, Bradley KM, Hoshika S, Jiménez E, Zhang L, et al. (January 2014). "In vitro selection with artificial expanded genetic information systems". Proceedings of the National Academy of Sciences of the United States of America. 111 (4): 1449–1454. Bibcode:2014PNAS..111.1449S. doi: 10.1073/pnas.1311778111 . PMC   3910645 . PMID   24379378.
  13. ↑ Pezo V, Liu FW, Abramov M, Froeyen M, Herdewijn P, Marlière P (July 2013). "Binary genetic cassettes for selecting XNA-templated DNA synthesis in vivo". Angewandte Chemie. 52 (31): 8139–8143. doi:10.1002/anie.201303288. PMID   23804524.
  14. ↑ Taylor AI, Pinheiro VB, Smola MJ, Morgunov AS, Peak-Chew S, Cozens C, et al. (February 2015). "Catalysts from synthetic genetic polymers". Nature. 518 (7539): 427–430. Bibcode:2015Natur.518..427T. doi:10.1038/nature13982. PMC   4336857 . PMID   25470036.
  15. 1 2 Sun Q, Pastor L, Du J, Powell MJ, Zhang A, Bodmer W, et al. (5 October 2021). "A novel xenonucleic acid-mediated molecular clamping technology for early colorectal cancer screening". PLOS ONE. 16 (10): e0244332. Bibcode:2021PLoSO..1644332S. doi: 10.1371/journal.pone.0244332 . PMC   8491914 . PMID   34610014.
  16. ↑ D'Agata R, Giuffrida MC, Spoto G (November 2017). "Peptide Nucleic Acid-Based Biosensors for Cancer Diagnosis". Molecules. 22 (11): 1951. doi: 10.3390/molecules22111951 . PMC   6150339 . PMID   29137122.
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