DNA Polymerase Template Interactions Probed by Degenerate Isosteric Nucleobase Analogs

Paul, Natasha; Nashine, Vishal; Zhang, Peiming; Zhou, Jie; Bergstrom, Donald E.; Davisson, V. Jo

doi:10.1016/j.chembiol.2003.08.008

Cited by 36 publications

(37 citation statements)

References 55 publications

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“…In one study, it was found that the fluorinated bases prefer to pair with themselves relative to the natural bases, similar to results seen by Kool in DNA [13, 14]. Davisson collected evidence on the roles of sterics and electrostatics in DNA synthesis using azole carboxamide base analogues [39]. McLaughlin has designed analogues lacking minor groove hydrogen bond acceptors to explore the roles of minor groove solvation in DNA stability [40].…”

Section: Why Modify Dna Bases?mentioning

confidence: 83%

Redesigning the Architecture of the Base Pair: Toward Biochemical and Biological Function of New Genetic Sets

Krueger

Kool

2009

Chemistry & Biology

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Recognition of the nucleic acid bases within the DNA scaffold comprises the basis for transmission of genetic information, dictating protein and cell assembly, organismal development, and evolution. Driven in part by the need to test our current understanding of this information transfer, chemists have begun to design and synthesize nonnatural bases and base pair structures to mimic the function of DNA without relying on Nature’s purine-pyrimidine base pair scaffold. Multiple examples have been recently described of new genetic architectures that self-assemble stably and sequence specifically in vitro, and experiments with polymerases in vitro show that at least isolated unnatural base pairs can be replicated as well. Moreover, recent experiments with unnatural bases in bacterial cells have demonstrated surprisingly efficient reading of the chemical information. This suggests the future possibility of redesigning and replacing the chemical information of an evolving cell while retaining biological function. Such unnatural base pair components, whether recognized by nature or not, are already proving useful in biotechnology. In addition to practical applications, this chemical approach also gives basic insight into the forces and mechanisms that govern DNA structure and replication.

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Section: Why Modify Dna Bases?mentioning

confidence: 83%

Redesigning the Architecture of the Base Pair: Toward Biochemical and Biological Function of New Genetic Sets

Krueger

Kool

2009

Chemistry & Biology

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“…Azole heterocyclic carboxamides can act as nucleobase mimics and, in fact, structurally can take on the appearance of either purines or pyrimidines (Figure 6) [91]. Because these analogs are small, they have some molecular mobility and can shift in order to adjust the hydrogen bonding patterns and electronic interactions to allow pairing with different bases [91].…”

Section: Purine/pyrimidine Mimicsmentioning

confidence: 99%

Synthetic Nucleotides as Probes of DNA Polymerase Specificity

Walsh

Beuning

2012

Journal of Nucleic Acids

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The genetic code is continuously expanding with new nucleobases designed to suit specific research needs. These synthetic nucleotides are used to study DNA polymerase dynamics and specificity and may even inhibit DNA polymerase activity. The availability of an increasing chemical diversity of nucleotides allows questions of utilization by different DNA polymerases to be addressed. Much of the work in this area deals with the A family DNA polymerases, for example, Escherichia coli DNA polymerase I, which are DNA polymerases involved in replication and whose fidelity is relatively high, but more recent work includes other families of polymerases, including the Y family, whose members are known to be error prone. This paper focuses on the ability of DNA polymerases to utilize nonnatural nucleotides in DNA templates or as the incoming nucleoside triphosphates. Beyond the utility of nonnatural nucleotides as probes of DNA polymerase specificity, such entities can also provide insight into the functions of DNA polymerases when encountering DNA that is damaged by natural agents. Thus, synthetic nucleotides provide insight into how polymerases deal with nonnatural nucleotides as well as into the mutagenic potential of nonnatural nucleotides.

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“…In this design, the pyrazole-3-carboxamide was changed to a class of triazoles that include (1H)-1,2,3-triazole-4-carboxamide, (2H)-1,2,3-triazole-4-carboxamide, and 1,2,4-triazole-4-carboxamide (Figure 13B) [56]. All three analogs are rather promiscuous as each allows for the incorporation of multiple dNMPs.…”

Section: Who Needs Fidelity? Examples and Applications For The Promismentioning

confidence: 99%

“…All three analogs are rather promiscuous as each allows for the incorporation of multiple dNMPs. Of these three analogs, (1H)-1,2,3-triazole-4-carboxamide displays the highest degree of selectivity as the catalytic efficiency for incorporating dGMP is 10-fold higher than dAMP and greater than 50-fold more efficient than the incorporation of the pyrimidines dCMP or dTMP [56]. In contrast, 1,2,4-triazole-3-carboxamide and (2H)-1,2,3-triazole-4-carboxamide behave as universal nucleotides since nearly identical catalytic efficiencies are reported for the incorporation of various dNMPs.…”

Section: Who Needs Fidelity? Examples and Applications For The Promismentioning

confidence: 99%

Non-natural nucleotides as probes for the mechanism and fidelity of DNA polymerases

Lee

Berdis

2010

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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DNA is a remarkable macromolecule that functions primarily as the carrier of the genetic information of organisms ranging from viruses to bacteria to eukaryotes. The ability of DNA polymerases to efficiently and accurately replicate genetic material represents one of the most fundamental yet complex biological processes found in nature. The central dogma of DNA polymerization is that the efficiency and fidelity of this biological process is dependent upon proper hydrogen-bonding interactions between an incoming nucleotide and its templating partner. However, the foundation of this dogma has been recently challenged by the demonstration that DNA polymerases can effectively and, in some cases, selectively incorporate non-natural nucleotides lacking classic hydrogen-bonding capabilities into DNA. In this review, we describe the results of several laboratories that have employed a variety of non-natural nucleotide analogs to decipher the molecular mechanism of DNA polymerization. The use of various non-natural nucleotides has lead to the development of several different models that can explain how efficient DNA synthesis can occur in the absence of hydrogen-bonding interactions. These models include the influence of steric fit and shape complementarity, hydrophobicity and solvation energies, basestacking capabilities, and negative selection as alternatives to rules invoking simple recognition of hydrogen bonding patterns. Discussions are also provided regarding how the kinetics of primer extension and exonuclease proofreading activities associated with high-fidelity DNA polymerases are influenced by the absence of hydrogen-bonding functional groups exhibited by non-natural nucleotides.DNA polymerases are responsible for chromosome replication, and many play essential roles in DNA repair and recombination. These enzymes add mononucleotides onto the 3′-end of a primer strand using the complementary strand as a template ( Figure 1A). Viewing DNA in this simple two-dimensional projection gives the impression that hydrogen-bonding interactions between the template base and the base of the incoming nucleotides are the most powerful physical forces that stabilize the conformation and structure of nucleic acid. By inference, these hydrogen-bonding interactions are thought to be the primary determinants in base pair recognition during the polymerization reaction. In this case, the mutual recognition of adenine (A)1 by thymine (T) and of guanine (G) by cytosine (C) involves hydrogenbonding interactions between each partner ( Figure 1B). At the atomic level, the non-sp2

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DNA Polymerase Template Interactions Probed by Degenerate Isosteric Nucleobase Analogs

Cited by 36 publications

References 55 publications

Redesigning the Architecture of the Base Pair: Toward Biochemical and Biological Function of New Genetic Sets

Redesigning the Architecture of the Base Pair: Toward Biochemical and Biological Function of New Genetic Sets

Synthetic Nucleotides as Probes of DNA Polymerase Specificity

Non-natural nucleotides as probes for the mechanism and fidelity of DNA polymerases

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