Other Sequence Contexts

The structures of aromatic amine adducts have also been studied in other sequence contexts [26, 27]. The dG-C8-AP adduct at a single/double-strand junction, which models the situation at a replication fork, shares the features of the S-conformation, regardless of whether there is a dC partner, a mismatched dA, or no base opposite the lesion. The modified dG is displaced into the major groove, 

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In order to test the hypothesis that efficient promoter sequences will be more likely to acquire an A-DNA like conformation than other sequences, we carried out a collection of molecular dynamics simulations of the DNA double stranded dodecamers listed in Table 3. All these simulations were done with the CHARMM23 potential [93], in the presence of explicit solvent (-3500 TIP3 [99] water molecules) and 22 sodium ions (the simulation protocol is detailed in [89,100,101]). The DNA sequences were chosen to include known functional promoters (MLP, MLP2, AT, E4, 6T, CYCl, EFIA, and R28), nonfunctional promoters which could function with a mutant TBP (2C and 7G) [69,70], an inosine variant which can promote transcription (I) [102], and negative controls (GC, POLYA). This collection of sequences also includes two pairs of TATA boxes located in different contexts (MLP and MLP2, and AT and E4) in order to explore the sensitivity of the results to end effects. All the simulations started from a canonical B-DNA conformation and relaxed into a structure closer to A-DNA after 2 ns of simulation, not all the sequences achieved the same structure, as shown in Table 3, an indication that the simulation protocol is capable of identifying sequence dependent features. 

Attack points are metal ion centers and specific cysteine residues of proteins. The mechanisms by which cysteine nitrosylation regulates protein functions can be broadly described in allosteric terms similar to protein phosphorylation. Often, 02-mediated redox reactions cooperate in the allosteric control by NO of protein functions. S-nitrosylation of target proteins is a redox-based signal with exquisite specificity based on the selective modification of single cysteine residues. The selectivity of S-nitrosylation has been shown to be provided by both the subcellular distribution of NOS enzymes and the sequence context of cysteine residues in target proteins. Two nitrosylation motifs have been identified. In one motif, the target cysteine is located between an acidic and a basic amino acid, as revealed in either the primary sequence or the tertiary structure. In the other motif, the cysteine is contained in a hydrophobic region. 

Extensive studies by NMR methods have shown that the conformations of PAH diol epoxide-N2-dG and - N6-dA adducts in double-stranded DNA depend markedly on the stereochemistry, PAH topology, and base sequence context Earlier work has been summarized by us [53]. Since then, we have published the NMR solution structures of a number of other DNA adducts [79, 88, 89, 92]. The structural properties of various DNA adducts have been reviewed more recently by Lukin and de los Santos [93]. The basic structural motifs, based on our work and that of others [94—98] that are relevant to the NER studies described in this chapter, are summarized in Figure 12.3. Computational analyses have provided insights into the origins and stereochemistry dependence of these remarkably different adduct conformations [26, 42, 47, 54, 99]. In the following, we summarize the main features of these different conformations. 

SH2 domains bind to peptides or sections of proteins that contain phosphotyrosine residues in particular sequence contexts. The formation of phosphorylated tyrosine residues in a receptor often results from hormone activation of the receptor. The phosphorylated tyrosine-containing peptides in the receptor can be recognized and bound by other proteins that have SH2 domains. The SH2 domain allows different proteins to respond to and be affected by the phosphorylated tyrosines that arise in proteins as a result of a signal transduction event. 

Like others genomic context methods, with the increasing number of completely sequenced genomes, it is expected that the accuracy of these predictions will be improved over time. 

The frequency of misincorporation is not only characteristic of a polymerase but is also subject to a number of faaors associated with reaction conditions. Most important is the nature of the nucleotide mismatches. The sequence context of the template-primer and other factors, such as symmetry of the mispair, rate of synthesis, and balance status of nucleotide (dNTP) pool, play a significant but secondary role. On the other hand, the mutagenic effect of Mn, when it replaces Mg, is primarily attributed to the perturbation in the mode of dNTP binding at the polymerase active site (7). 

Human errors may be dependent on the specific accident sequence displayed in the event tree, and, for that reason, may be included in the event tree. This requires the human-factors specialist to consider the context of the error in terms of stress, operator training in response to the accident, di.tgnosiic paiierns, environmental, and other performance-shaping factors. 

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