The Chemical Basis of Mutation

Le, Orgel

doi:10.1002/9780470122723.ch6

Cited by 8 publications

(3 citation statements)

References 131 publications

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“…Incorporation of dITP from the pools opposite template C is non-mutagenic, similar to the incorporation of dUTP 8; misincorporation of dXTP impedes the progression of replication 9. On the other hand, on the DNA level, the deamination of adenine to hypoxanthine or guanine to xanthine results in elevated mutagenesis 10; 11, because hypoxanthine pairs as G 12, and xanthine is a DNA replication blocking lesion. Irrespective of the route of appearance in DNA, both inosine and xanthine are recognized in most organisms by a specialized repair system initiated by the orthologs of endonuclease V 13 and elicit DNA repair reactions that lead to DNA fragmentation and genomic instability when the level of analogues is high 3; 14; 15.…”

Section: Introductionmentioning

confidence: 99%

Functional Study of the P32T ITPA Variant Associated with Drug Sensitivity in Humans

Stepchenkova

Tarakhovskaya

Spitler

et al. 2009

Journal of Molecular Biology

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Sanitization of the cellular nucleotide pools from mutagenic base analogs is necessary for the accuracy of transcription and replication of genetic material and plays a substantial role in cancer prevention. The undesirable mutagenic, recombinogenic and toxic incorporation of purine base analogs (i.e. ITP, dITP, XTP, dXTP or 6-hydroxyaminopurine (HAP) deoxynucleoside triphosphate) into nucleic acids is prevented by inosine triphosphate pyrophosphatase (ITPA). The ITPA gene is a highly conserved, moderately expressed gene. Defects in ITPA orthologs in model organisms cause severe sensitivity to HAP and chromosome fragmentation. A human polymorphic allele 94C->A encodes for the enzyme with a P32T amino acid change and leads to accumulation of non-hydrolyzed ITP. ITPase activity is not detected in erythrocytes of these patients. The P32T polymorphism has also been associated with adverse sensitivity to purine base analog drugs. We have found that the ITPA-P32T mutant is a dimer in solution, as is wild-type ITPA, and has normal ITPA activity in vitro, but the melting point of ITPA-P32T is 5 degrees C lower than that of wild-type. ITPA-P32T is also fully functional in vivo in model organisms as determined by a HAP mutagenesis assay and its complementation of a bacterial ITPA defect. The amount of ITPA protein detected by western blot is severely diminished in a human fibroblast cell line with the 94C->A change. We propose that the P32T mutation exerts its effect in certain human tissues by cumulative effects of destabilization of transcripts, protein stability and availability.

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Section: Introductionmentioning

confidence: 99%

Functional Study of the P32T ITPA Variant Associated with Drug Sensitivity in Humans

Stepchenkova

Tarakhovskaya

Spitler

et al. 2009

Journal of Molecular Biology

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“…[23] These reactions occur at the nucleic acid level and are responsible for the mutagenic action of NA. [24] Investigators have used the reaction of NA with tRNA to probe the structure and biological activity of tRNA. [25] HONO is an important source of the OH radical that may damage biomolecules.…”

Section: Introductionmentioning

confidence: 99%

“…Nitrous acid deaminates adenine, guanine, and cytosine derivatives, converting them to the corresponding hypoxanthine, xanthine, and uracil derivatives, respectively . These reactions occur at the nucleic acid level and are responsible for the mutagenic action of NA . Investigators have used the reaction of NA with tRNA to probe the structure and biological activity of tRNA .…”

Section: Introductionmentioning

confidence: 99%

Intermolecular interactions in uracil–nitrous acid complexes: structures, binding energy, topological properties, and nuclear magnetic resonance study

Makiabadi

Zakarianejad

Bagheri

et al. 2013

Int J of Quantum Chemistry

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Molecular interactions between uracil and nitrous acid (U-NA) [C 4 N 2 O 2 H 4 ANO 2 H] have been studied using B3LYP, B3PW91, and MP2 methods with different basis sets. The optimized geometries, harmonic vibrational frequencies, charge transfer, topological properties of electron density, nucleus-independent chemical shift (NICS), and nuclear magnetic resonance one-and two-bonds spin-spin coupling constants were calculated for U-NA complexes. In interaction between U and NA, eight cyclic complexes were obtained with two intermolecular hydrogen bonds N(C)HU…N(O) and OH NA …O U . In these complexes, uracil (U) simultaneously acts as proton acceptor and proton donor. The most stable complexes labeled, UNA1 and UNA2, are formed via NH bond of U with highest acidity and CO group of U with lowest proton affinity. There is a relationship between hydrogen bond distances and the corresponding frequency shifts. The solvent effect on complexes stability was examined using B3LYP method with the aug-cc-pVDZ basis set by applying the polarizable continuum model (PCM). The binding energies in the gas phase have also been compared with solvation energies computed using the PCM. Natural bond orbital analysis shows that in all complexes, the charge transfer takes place from U to NA. The results predict that the Lone Pair (LP)(O) U ! r*(OAH) and LP(N(O) NA ! r*(N(C)AH) U donor-acceptor interactions are most important interactions in these complexes. Atom in molecule analysis confirms that hydrogen bond contacts are electrostatic in nature and covalent nature of proton donor groups decreases upon complexation. The relationship between spin-spin coupling constant ( 1h J H … Y and 2h J H … Y ) with interaction energy and electronic density at corresponding hydrogen bond critical points and H-bonds distances are investigated. NICS used for indicating of aromaticity of U ring upon complexation.

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Use of mutagens in the improvement of production strains of microorganisms

Thoma¹

1971

Folia Microbiol

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The Chemical Basis of Mutation

Cited by 8 publications

References 131 publications

Functional Study of the P32T ITPA Variant Associated with Drug Sensitivity in Humans

Functional Study of the P32T ITPA Variant Associated with Drug Sensitivity in Humans

Intermolecular interactions in uracil–nitrous acid complexes: structures, binding energy, topological properties, and nuclear magnetic resonance study

Use of mutagens in the improvement of production strains of microorganisms

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