DNA Damage and Repair Sigma Aldrich. DNA Damage and Repair Mechanisms. Damage to cellular DNA is involved in mutagenesis and the development of cancer. The DNA in a human cell undergoes several thousand to a million damaging events per day, generated by both external exogenous and internal metabolic endogenous processes. Changes to the cellular genome can generate errors in the transcription of DNA and ensuing translation into proteins necessary for signaling and cellular function. Genomic mutations can also be carried over into daughter generations of cells if the mutation is not repaired prior to mitosis. Once cells lose their ability to effectively repair damaged DNA, there are three possible responses see Figure 1. The cell may become senescent, i. Epigenetic marks on the genome can be copied from one cell generation to the next, which may change gene expression, but not primary DNA sequence. DNA methylation is. Figure 1. The roles of DNA damage and DNA repair in cancer and aging. Inherited mutations in genes employed in DNA repair that give rise to syndromes characterized. Strand Dna Activation' title='12 Strand Dna Activation' />DNA Damage and Repair Mechanisms. Damage to cellular DNA is involved in mutagenesis and the development of cancer. The DNA in a human cell undergoes several thousand. The Light and the Shadow. Secret Government Spiritual Solutions by Anna Hayes Copyright 1999, Anna Hayes. Transcript of audio tape. We actually made it. Interdimensional 12 Strand DNA Activation connects you to your spiritual guideance, all living things, and the other twelve dimensions. In 2. 00. 5, multiple laboratories reported that senescence could occur in cancer cells in vivo as well as in vitro, stopping mitosis and preventing the cell from evolving further. The cell may become apoptotic. Sufficient DNA damage may trigger an apoptotic signaling cascade, forcing the cell into programmed cell death. The cell may become malignant, i. Figure 1. The pathway of cellular DNA damage and repair that leads to senescence, apoptosis, or cancer. To compensate for the degree and types of DNA damage that occur, cells have developed multiple repair processes including mismatch, base excision, and nucleotide excision repair mechanisms, with little process redundancy. Cells may have evolved to proceed into apoptosis or senescence if overwhelming damage occurs rather than expend energy to effectively repair the damage. The rate at which a cell is able to make repairs is contingent on factors including cell type and cell age. Sources of DNA Damage. For many years, exogenous sources of damage have been thought to be the primary cause of DNA mutations leading to cancer. However, Jackson and Loeb proposed that endogenous sources of DNA damage also contribute significantly to mutations that lead to malignancy. Both environmental and cellular sources can result in similar types of DNA damage. DNA can be attacked by physical and chemical mutagens. Physical mutagens are primarily radiation sources, including UV 2. UV radiation produces covalent bonds that crosslink adjacent pyrimidine cytosine and thymine bases in the DNA strand. Ionizing radiation X rays initiates DNA mutations by generating free radicals within the cell that create reactive oxygen species ROS and result in single strand and double strand breaks in the double helix. Chemical mutagens can attach alkyl groups covalently to DNA bases nitrogen mustard compounds that can methylate or ethylate the DNA base are examples of DNA alkylating agents. Strand Dna Activation' title='12 Strand Dna Activation' />Procarcinogens are chemically inert precursors that are metabolically converted into highly reactive carcinogens. These carcinogens can react with DNA by forming DNA adducts, i. DNA. Benzoapyrene, a polyaromatic heterocycle, is not itself carcinogenic. It undergoes two sequential oxidation reactions mediated by cytochrome P4. BPDE, the carcinogenic metabolite that is able to form a covalent DNA adduct see Figure 2. Figure 2. Benzoapyrene is oxidized by P4. DNA damage can also result from endogenous metabolic and biochemical reactions, some of which are not well understood. Sega Mega Drive Collection Pc more. Hydrolysis reactions can partially or completely cleave the nucleotide base from the DNA strand. The chemical bond connecting a purine base adenine or guanine to the deoxyribosyl phosphate chain can spontaneously break in the process known as depurination. An estimated 1. 0,0. Depyrimidination loss of pyrimidine base from thymine or cytosine also occurs, but at a rate 2. Deamination occurs within the cell with the loss of amine groups from adenine, guanine, and cytosine rings, resulting in hypoxanthine, xanthine, and uracil, respectively. DNA repair enzymes are able to recognize and correct these unnatural bases. However, an uncorrected uracil base may be misread as a thymine during subsequent DNA replication and generate a CT point mutation. Strand Dna Activation' title='12 Strand Dna Activation' />DNA methylation, a specific form of alkylation, occurs within the cell due to a reaction with S adenosyl methionine SAM. SAM is an intracellular metabolic intermediate that contains a highly reactive methyl group. In mammalian cells, methylation occurs at the 5 position of the cytosine ring of a cytidine base C that is 5 to a guanosine base G, i. Cp. G. A significant source of mutation error is the spontaneous deamination of the 5 methylcytosine product of methyl ation. Loss of the amine group results in a thymine base, which is not detected by DNA repair enzymes as an unnatural base. The resulting substitution is retained in DNA replication, creating a CT point mutation see Figure 3. Figure 3. The 2 phase mutation of cytosine results in thymine, creating a CT point mutation. Normal metabolic processes generate reactive oxygen species ROS, which modify bases by oxidation. Both purine and pyrimidine bases are subject to oxidation. The most common mutation is guanine oxidized to 8 oxo 7,8 dihydroguanine, resulting in the nucleotide 8 oxo deoxy guano sine 8 oxo d. G. The 8 oxo d. G is capable of base pairing with deoxyadenosine, instead of pairing with deoxycytotidine as expected. If this error is not detected and corrected by mismatch repair enzymes, the DNA subsequently replicated will contain a CA point mutation. ROS may also cause depurination, depyrimidination, and single strand or double strand breaks in the DNA. Other genomic mutations may be introduced during DNA replication in the S phase of the cell cycle. Polymerases that duplicate template DNA have a small but significant error rate, and may incorporate an incorrect nucleotide based on Watson Crick pairing versus the template DNA. Chemically altered nucleotide precursors may be incorporated into the generated DNA by the polymerase, instead of normal bases. In addition, polymerases are prone to stuttering when copying sections of DNA that contain a large number of repeating nucleotides or repeating sequences microsatellite regions. This enzymatic stuttering is due to a strand slippage, when the template and replicated strands of DNA slip out of proper alignment. As a result, the polymerase fails to insert the correct number of nucleotides indicated by the template DNA, resulting in too few or too many nucleotides in the daughter strand. Single strand and double strand cleavage of the DNA may occur. Single strand breaks may result from damage to the deoxyribose moiety of the DNA deoxyribosylphosphate chain. Breaks also result as an intermediate step of the base excision repair pathway after the removal of deoxyribose phosphate by AP endonuclease 1. When a single strand break occurs, both the nucleotide base and the deoxyribose backbone are lost from the DNA structure. Double strand cleavage most often occurs when the cell is passing through S phase, as the DNA may be more susceptible to breakage while it is unraveling for use as a template for replication. Mechanisms of DNA Repair. While the cell is able to evolve into either an apoptotic or senescent state, these actions are performed as a last resort. For each type of DNA damage, the cell has evolved a specific method of repairing the damage or eliminating the damaging compound. O6 Methylguanine DNA methyltransferase MGMT DNA alkyltransferase cleaves both methyl and ethyl adducts from guanine bases on the DNA structure.