Repair, mutations

One possibility is that there is differential susceptibility to both mutation and killing among the cells. If, for example, there are two populations of cells, the high-dose data reflect the mutation rate of the component more resistant to killing. If these cells are also resistant to mutation, the resistance of the total cell population is underestimated. Another possibility is that there is a mutation-repair mechanism that is turned on at high doses. Deviations from either of these causes can usually be detected by the shape and slope of the curve at high doses for example, linear extrapolation from high-dose... 

Other microbial mutation, repair and recombination assays have also been used in chemical screening, however, the data base for carcinogenicity-mutagenicity correlation established with these in vitro test systems is relatively limited at this time.62-70 At present, the Ames Salmonella assay appears to be the most generally applicable screen for the detection of chemical mutagens. No other mutagenesis assay has been shown to respond to such a wide group of chemical types as the Salmonella mutants. 

Which is the most correct sequence of events in gene repair mechanisms in patients without a mutated repair process ... 

Damage to DNA molecules also causes mutations. Repair mechanisms correct DNA damage, usually by removing and replacing the damaged region. The intact, undamaged strand serves as a template for the DNA polymerase involved in the repair process. 

Mouse visible or eleetrophoretie specifie-locus tests Assays for skeletal and cataract mutations Cytogenetic analy.sis and heritable translocation assays DNA damage and repair in rodent germ cells Dominant lethal assay... 

If enzymes responsible for DNA repair are unable to remove the DNA adduct, or if an error takes place in the repair, then the error in the genetic code remains when the cell divides. Thus, cellular proliferation is also required, in addition to a mutation, for there to be a permanent effect of a chemical compound. Accumulation of genetic errors, i.e., mutations, has been suspected to be an important factor in chemical carcinogenesis. ... 

The in vivo relevance and biological importance of in vitro observations about mast cell function, as well as the contributions of mast cells towards the expression of particular biological responses (such as various models of anaphylaxis) in vivo, can be assessed using c-kit mutant mice (e.g., WBB6Fi-FCit or mice) that virtually lack mast cell populations. Mice with mutations of c-kit [6,11] or mutations that affect KIT expression [12-14] have other abnormalities of phenotype besides a mast cell deficiency. However, the mast cell deficiency of these mice can be selectively repaired by the adoptive transfer of genetically compatible, in vitro-derived... 

Rephcation errors, even with a very efficient repair system, lead to the accumulation of mutations. A human has 10 nucleated cells each with 3 X 10 base pairs of DNA. If about 10 cell divisions occur in a lifetime and 10 mutations per base pair per cell generation escape repair, there may evenmaUy be as many as one mutation per 10 bp in the genome. Formnately, most of these will probably occur in DNA that does not encode proteins or will not affect the function of encoded proteins and so are of no consequence. In addition, spontaneous and chemically induced damage to DNA must be repaired. 

Figure 36-22. Mismatch repair of DNA. This mechanism corrects a single mismatch base pair (eg, C to A rather than T to A) or a short region of unpaired DNA. The defective region is recognized by an endonuclease that makes a single-strand cut at an adjacent methylated GATC sequence. The DNA strand is removed through the mutation, replaced, and religated.

Another cumulative effect of radiation can be an irreversible alteration of DNA sequences. If part of a DNA molecule is ionized, its molecular chain may be broken. Chain breaks are repaired in the body, but after a serious rupture, the repaired unit may have a different sequence. This type of changed sequence is a genetic mutation. Altered DNA sequences in the reproductive organs are transmitted faithfully, thus passing on the genetic mutations to fiature generations. Because these effects are cumulative, individuals of childbearing age need to be especially carefial about radiation exposure. 

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. 

Cellular changes may result in cell death, which if extensive, may produce irreversible damage to an organ or tissue or may result in the death of the individual. If the cell recovers, altered metabolism and function may still occur, which may be repaired or may result in the manifestation of clinical symptoms. These changes may also be expressed at a later time as tumors or cellular mutations, which may result in abnormal tissue. 

DNA CT also permits chemistry at a distance. Oxidative DNA damage and thymine dimer repair can proceed in a DNA-mediated reaction initiated from a remote site. These reactions too are sensitive to intervening DNA dynamical structure, and such structures can serve to modulate DNA CT chemistry. The sensitivity of DNA CT to base pair stacking also provides the basis for the design of new DNA diagnostics, tools to detect mutations in DNA and to probe protein-DNA interactions. 

---