DNA replication proteins

Molecular complexation is a precondition for receptor functions such as substrate selection, substrate transportation, isomeric differentiation, and stereoselective catalysis. Although the investigation of such functions with synthetically derived compounds is a relatively new development in chemistry, they are well known and extensively studied functions in the biological domain. Evolution, gene expression, cell division, DNA replication, protein synthesis, immunological response, hormonal control, ion transportation, and enzymic catalysis are only some of the many examples where molecular complexation is a prerequisite for observing a biological process. 

Caridha D, Kathcart AK, Jirage D, Waters NC (2010) Activity of substituted thiophene sulfonamides against malarial and mammalian cyclin dependent protein kinases. Bioorg Med Chem Lett 20(13) 3863-3867 Geyer JA, Keenan SM, Woodard CL et al (2009) Selective inhibition of Pfinrk, a Plasmodium falciparum CDK, by antimalarial l,3-diaryl-2-propenones. Bioorg Med Chem Lett 19(7) 1982-1985 Jirage D, Chen Y, Caridha D et al (2010) The malarial CDK Pfinrk and its effector PfMATl phosphorylate DNA replication proteins and co-localize in the nucleus. Mol Biochem Parasitol 172(1) 9-18... 

Eukaryotic DNA polymerases have also been isolated and characterized as listed in Table 22.1. Based on studies of SV40 DNA replication in vitro, it has been found that DNA polymerase d has high processivity and is required for leading-strand synthesis, making it analogous to E. coli DNA pol III. DNA polymerase d requires ATP and is stimulated by two additional DNA replication proteins, RF-C and PCNA. DNA polymerase a serves the same role as E. coli DNA pol I in that DNA polymerase a is necessary for lagging-strand synthesis. In addition to DNA polymerase a and d, three other DNA polymerizing activities have been identified. DNA polymerase I is involved in DNA repair and is most similar to E. coli DNA pol II. DNA polymerase b is also a repair enzyme, and DNA polymerase g is required for mitochondrial DNA synthesis. 

Johnson CE, England PT. Changes in organization of Crithidia fasdculata kinetoplast DNA replication proteins durii the cell cyde. J Cell Biol 1998 143(4) 911-9. 

Frouin 1, Montecucco A, Biamond G et al. Cell cycle-dependent dynamic association of cyclin/ Cdk complexes with human DNA replication proteins. EMBO J 2002 21 2485-2495. 

The assay conditions provided below should be considered as starting points for further optimization. As the optimal conditions for each activity may differ, researchers are encouraged to optimize salt concentration, pH, template concentration, and temperature for each DNA polymerase in each assay. A thorough review of assay methods for mesophilic DNA polymerases can be found in a Methods of Enzymology volume devoted entirely to DNA replication proteins. ... 

The success of modern biochemistry in explaining such processes as DNA replication, protein biosynthesis, and enzyme catalysis is a direct result of developments in preparatory, instrumental, and computational procedures that have led to the determination of large numbers of structures of biological macromolecules by techniques based on X-ray diffraction. 

Liptak, L.M., Uprichard, S.L. and Knipe, D.M., Functional order of assembly of herpes simplex virus DNA replication proteins into prereplicative site structures. J. Virol, 70, 1759-1767 (1996). 

Once the broad outlines of DNA replication and protein biosynthesis were established scien tists speculated about how these outlines af fected various origins of life scenarios A key question concerned the fact that proteins are re quired for the synthesis of DNA yet the synthesis of these proteins is coded for by DNA Which came first DNA or proteins How could DNA store genetic infor mation if there were no enzymes to catalyze the polymerization of its nucleotide components How could there be proteins if there were no DNA to code for them ... 

Even if It could be shown that RNA preceded both DNA and proteins in the march toward living things that doesn t automatically make RNA the first self replicating molecule Another possibility is that a self replicating polynucleotide based on some carbo hydrate other than o ribose was a precursor to RNA Over many generations natural selection could have led to the replacement of the other carbohydrate by D ribose giving RNA Recent research on unnatural polynucleotides by Professor Albert Eschenmoser of the Swiss Federal Institute of Technology (Zurich) has shown for example that nucleic acids based on L threose possess many of the properties of RNA and DNA... 

Cross-linkage - bifunctional agents may form covalent bonds with each of two adjacent guanine residues and such inter-strand cross-links will lead to inhibition of DNA replication and transcription. Intra-strand and DNA-protein cross-links may also be formed ... 

When induced in macrophages, iNOS produces large amounts of NO which represents a major cytotoxic principle of those cells. Due to its affinity to protein-bound iron, NO can inhibit a number of key enzymes that contain iron in their catalytic centers. These include ribonucleotide reductase (rate-limiting in DNA replication), iron-sulfur cluster-dependent enzymes (complex I and II) involved in mitochondrial electron transport and cis-aconitase in the citric acid cycle. In addition, higher concentrations of NO,... 

The core unit of the chromatin, the nucleosome, consists of histones arranged as an octamer consisting of a (H3/ H4)2-tetramer complexed with two histone H2A/H2B dimers. Accessibility to DNA-binding proteins (for replication, repair, or transcription) is achieved by posttranslational modifications of the amino-termini of the histones, the histone tails phosphorylation, acetylation, methylation, ubiquitination, and sumoyla-tion. Especially acetylation of histone tails has been linked to transcriptional activation, leading to weakened interaction of the core complexes with DNA and subsequently to decondensation of chromatin. In contrast, deacetylation leads to transcriptional repression. As mentioned above, transcriptional coactivators either possess HAT activity or recruit HATs. HDACs in turn act as corepressors. 

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