DNA replication errors

Mismatched base (Gj) DNA replication errors A mutation on one of two genes, hMSH2 or hMLHl, initiates defective repair of DNA mismatches, resulting in a condition known as hereditary nonpolyposis colorectal cancer— HNPCC. DNA polymerase DNA ligase... 

Bischoff DS, Slavicek JM (1997b), Phenotypic and genetic analysis of Lymantria dispar nucleopolyhedrovirus few polyhedra mutants mutations in the 25K FP gene may be caused by DNA replication errors, J. Virol. 71 1097-1106. 

For non-DNA-reactive chemicals, the only differences would be that there would be no need for binding of the parent chemical or a metabolite to DNA— all olher steps could be the same. There might be additional differences in cases where a chemical does not interact with DNA directly or indirectly (for example, via reactive oxygen species). The DNA replication errors as a key event would still hold for non-DNA-reactive chemicals it is just that the chemically produced mutations arise from an enhanced probability of replication errors as a result of increased cell proUferation in response to cytotoxicity as opposed to being from a more damaged DNA template, which is the case for DNA-reactive chemicals. 

There are many endogenous processes that change the information content of the DNA. These processes are inseparable from the performance and characteristics of an organism, and they are influenced by external factors to only a small extent. DNA replication errors... 

Goggins M, Offerhaus GJ, Hilgers W, et al. Pancreatic adenocarcinomas with DNA replication errors (RER+) are associated with wild-type K-ras and characteristic histopathology. Poor differentiation, a syncytial growth pattern, and pushing borders suggest RER+. Am J Pathol. 1998 152 1501-1507. 

Shcherbakova, P. V., and Pavlov, Y. I. (1996). 3 —>5 exonucleases of DNA polymerases epsilon and delta correct base analog induced DNA replication errors on opposite DNA strands in Saccharomyces cerevisiae. Genetics 142, 717-726. 

Some nucleases are capable of hydrolyzing a nucleotide only when it is present at a terminal of a molecule these ate tefetted to as exonucleases. Exonucleases act in one direction (3 —> 5 ot 5 —> 30 only. In bacteria, a 3 —> 5 exonuclease is an integral part of the DNA replication machinery and there serves to edit— or proofread—the most recently added deoxynucleo-tide for base-pairing errors. 

A number of different DNA polymerase molecules engage in DNA replication. These share three important properties (1) chain elongation, (2) processivity, and (3) proofreading. Chain elongation accounts for the rate (in nucleotides per second) at which polymerization occurs. Processivity is an expression of the number of nucleotides added to the nascent chain before the polymerase disengages from the template. The proofreading function identifies copying errors and corrects them. In E coli, polymerase III (pol III) functions at the... 

The maintenance of the integrity of the information in DNA molecules is of utmost importance to the survival of a particular organism as well as to survival of the species. Thus, it can be concluded that surviving species have evolved mechanisms for repairing DNA damage occurring as a result of either replication errors or environmental insults. 

DNA mismatch repair genes Genes that identify and correct errors in DNA base pairs during DNA replication. Mutations in the mismatch repair genes can lead to cancer by allowing abnormal cells to continue to grow. 

Induced mutagenesis in Escherichia coli is an active process involving proteins with DNA replication, repair, and recombination functions. The available evidence suggests that mutations are generated at sites where DNA has been damaged and that they arise via an error-prone repair activity. In an attempt to understand what specific contributions to mutagenesis are made by DNA lesions, we have studied the mutational specificity of some carcinogens, such as benzo[a]pyrene and aflatoxin, whose chemical reactions with DNA are... 

Mismatch Repair. Mispairs that break the normal base-pairing rules can arise spontaneously due to DNA biosynthetic errors, events associated with genetic recombination and the deamination of methylated cytosine (Modrich, 1987). With the latter, when cytosine deaminates to uracil, an endonuclease enzyme, /V-uracil-DNA glycosylase (Lindahl, 1979), excises the uracil residue before it can pair with adenine at the next replication. However, 5-methyl cytosine deaminates to form thymine and will not be excised by a glycosylase. As a result, thymine exits on one strand paired with guanine on the sister strand, that is, a mismatch. This will result in a spontaneous point mutation if left unrepaired. For this reason, methylated cytosines form spontaneous mutation hot-spots (Miller, 1985). The cell is able to repair mismatches by being able to distinguish between the DNA strand that exists before replication and a newly synthesized strand. 

One fascinating observation is that PCNA (proliferating cell nuclear antigen) can be modified by multiple forms of ubiquitin, demonstrating that DUBs with different specificities can act at the same location on a specific substrate. PCNA can be modified by mono-ubiquitin, 63-linked polyubiquitin, or SUMO at K164 [89]. Modification of PCNA by mono- or polyubiquitin determines whether it is utilized in translesion synthesis or error-free DNA repair, respectively. SUMO modification prevents PCNA function in DNA repair and instead promotes DNA replication. It is probable that multiple DUBs, as yet unidentified, are required to regulate PCNA modification. 

The observation that bile acids cause DNA damage (Table 3.4) suggests that bile acids should increase the frequency of mutation since unrepaired DNA damage causes replication errors. Table 3.5 lists the studies showing that bile acids cause an increase in mutant cells in the GI tract. In vitro, DOC treatment... 

Mutations can arise as a result of physical or chemical effects, or they can be due to accidental errors in DNA replication and recombination. 

Errors in DNA replication can produce a variety of mutations by failure of proofreading mechanisms. 

All organisms suffer a certain number of mutations as the result of errors in normal cellular operations such as DNA replication. The majority of such mutations are quickly recognized and corrected by specific enzymes that are capable of comparing the two complementary bases on the DNA molecule as replication proceeds. Occasionally, they are not detected and corrected fortunately, these spontaneous mutations are quite rare. The natural incidence of mutations can be increased by exposure to various environmental factors, and the effectiveness of a mutagen is assessed by the degree to which it increases the rate of mutation. 

Replication of DNA does not occur with complete precision, but rather has an intrinsic inaccuracy. The error rate for incorporation of nucleotides in DNA replication is of the order of one error per 10 - 10 correctly incorporated nucleotides. 

The genetic consequence of BaP-N2-guanine adduct formation can be associated with errors in base pairing during DNA replication, for example, base substitutions. 

Modifications to the base(s) of DNA with large adducts can cause misreading of the code during translation or replication and therefore mutations or affect the action of polymerases or alternatively can stimulate DNA repair, which could be error prone. Alkylation of bases may cause mispairing at DNA replication and so mutations in the daughter cells. 

Mutations caused by chemicals are mostly due to errors of DNA replication on a damaged template. Repair therefore is critical as if this occurs efficiently and before replication,... 

During the process of DNA replication, the normal rate of error is remarkably low, but errors still occur. Consequently, the cell has a system for repairing errors (Fig. 6.46) occurring during cell division when chromosomal DNA sequences are replicated by one of a series of polymerases. This is carried out by mismatch repair enzymes, which monitor and detect miscopied new DNA sequences. However, these repair processes are generally for normal bases put in the wrong place or the wrong number of bases in a repeat sequence. 

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