That is to say, the model to be simulated is a chain of non-linear oscillators, the four types of which can be identified with the Adenine (A), Cytosine (C), Guanine (G), and Thymine (T) or Uracil (C) components DNA, all having different spatial structures and masses, and where there is a travelling window opened in the double helix.
Imagine now that the DNA forms such a kind of pendulum, whilst the intertwined helices/chains are opened at one particular section to provide the travelling window, as in the previous figure.
Furthermore, studies of tRNA-tRNA interactions on ribosomes are presented in ; they offer full confirmation of our model, in which we consider an amino-acid-loaded tRNA complex as the predecessor of a protein.
This is a remote influence, connected with the protein synthesis continuum; it’s also an example of the genetic apparatus’ non-local functions, whereby the protein-synthesizing apparatus recognizes mRNA not only in parts (by nucleotides, locally), but in one piece (non-locally) as well.
Here, the translation context effect is clearly seen as a strategic influence of distant mRNA codons on the inclusion (or non-inclusion) of certain amino acids in the composition of a protein being synthesized.
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A large number of mammalian DNA polymerases have been identified within the last 3 years, and initial characterization suggests that they possess a surprisingly diverse array of substrate specificities. We investigate here the substrate specificity of one of these recently described polymerases, polymerase mu (pol μ).
Phosphoramidites that allow the generation of oligonucleotides containing site-specific lesions have been vital components for studying the mechanism of DNA repair. New DNA lesions are still being discovered and the study of their biological consequences will require their site-specific incorporation into oligonucleotides. The authors conclude that the increased availability of phosphoramidites for the synthesis of lesion-containing oligonucleotides should facilitate many future discoveries in the broad area of DNA damage and repair.
A directed approach to the delivery of therapeutic oligonucleotides specifically to the liver has been to target the asialoglycoprotein receptor (ASGPR) using a suitable glycoconjugate. Indeed, ASGPR is the ideal target for delivery of therapeutic oligonucleotides to the liver since it combines tissue specificity, high expression levels and rapid internalization and turnover. The use of oligonucleotide glycoconjugates has led to significant advances in therapeutic delivery as evidenced by the work of Alnylam Pharmaceuticals and Ionis Pharmaceuticals using multivalent N-acetylgalactosamine (GalNAc) oligonucleotide conjugates.
TdT's substrate specificity is uniquely suited for its role in promoting diversity in V(D)J recombination. TdT is template independent, adding random nucleotides only to 3′ single-stranded or blunt DNA ends (reviewed in reference ). Indeed, TdT shows generally reduced specificity in substrate selection, efficiently utilizing even triphosphate esters with nonnucleoside groups (e.g., p-nitrophenylethyl triphosphate) (). TdT thus can incorporate both ribonucleotides and deoxynucleotides during synthesis with similar efficiency in vitro (, , , ). Ribonucleotide incorporation may be tolerated in vivo due to the combination of TdT's highly restricted expression pattern and the beneficial impact of this enzyme on diversification of the immune repertoire.
Experiments in Fig. were supplemented with 0.1 mM ATP and 0.05 U of T4 ligase (Roche). After reactions were stopped with 20 mM EDTA, KOH was added to 0.3 M, and reaction mixtures were incubated for 2 h at 55°C and analyzed by denaturing PAGE as described above. Experiments in Table were performed as for Fig. , except that a mix of all eight nucleotides at the concentrations noted in Table was added (), MgCl2 was added to 10 mM, and the reaction time was 5 min. All detection and quantification of radiolabeled DNA were performed with a PhosphorImager and ImageQuanNT software (Molecular Dynamics).
The authors note that the detailed studies of the molecular mechanisms of DNA repair pathways were made possible by using site-specifically modified oligonucleotides and that the availability of phosphoramidites to synthesize oligonucleotides with DNA lesions has contributed to the field. They illustrate the article using primarily structural studies in the following examples: