Radiation Hormesis in Cancer
T. D. Luckey in Radiation Hormesis, 2020
Cellular repair mechanisms have also been observed to support hormesis. The well known example is DNA repair; this is replete with identified enzymes and metabolic reactions. DNA repair fails when: (1) a break occurs in the chromosome of a cell which is monoploid, e.g., an unfertilized egg or sperm cell which have only single stranded DNA, (2) relatively simultaneous breaks occur in both strands of DNA in the same area of a given chromosome, (3) a break occurs in one strand where the other carries a recessive gene for cancer or other disease, and (4) defective DNA is added to the chromosome from a viral infection. Failure to properly repair a break in DNA may allow any one of about 30 normal genes to be subtly transformed into an oncogene.22,924 Since each of our 50,000 genes contains 20,000 to 100,000 base pairs in a DNA chain, there is a big variety of combinations which can change normal genes into oncogenes. An oncogene releases the cell replication machinery from the limits which normally restrain growth. Some suspect the 30+ oncogenes have a common mechanism of action.982 A single cell can produce a well-defined tumor or form a metastasizing clone to establish cancer far removed from its original tissue.
Introduction to Genomics
Altuna Akalin in Computational Genomics with R, 2020
Mutations in the genome occur due to multiple reasons. First, DNA replication is not an error-free process. Before a cell division, the DNA is replicated with 1 mistake per 10^8 to 10^10 base-pairs. Second, mutagens such as UV light can induce mutations on the genome. The third factor that contributes to mutation is imperfect DNA repair. Every day, any human cell suffers multiple instances of DNA damage. DNA repair enzymes are there to cope with this damage but they are also not error-free, depending on which DNA repair mechanism is used (there are multiple), mistakes will be made at varying rates.
Notes on Cancer
Nate F. Cardarelli in The Thymus in Health and Senescence, 2019
Modern thinking has it that two distinct processes occur in chemical carcinogenesis.80Initiation, whereby a normal cell is transformed into a neoplastic cell, followed by promotion as the neoplastic single cell develops into a tumor. Both an initiator and a promoter must be available. Thus, carcinogens, per se, do not cause cancer.81 They must of course, penetrate the cell wall. Once within the cell, a molecular modification occurs, detoxifying enzymes that incorrectly alter the carcinogen within the cell then cause chemical rearrangements allowing it to penetrate the nuclear membrane. Binding to DNA follows, probably by forming covalent adducts termed “genotoxic carcinogens”. Normally the DNA repair mechanism functions and enzymes detach the agent from the DNA. However, if mitosis occurs prior to repair, abnormal DNA is copied, and a mutated gene is now firmly fixed in the genome. Mutation must occur on the “right” gene for cancer to occur. The key mutation is the one that turns off the cell’s apparatus for regulation of growth.
Possible modifier genes in the variation of neurofibromatosis type 1 clinical phenotypes
Published in Journal of Neurogenetics, 2018
DNA repair is a series of mechanisms that protect the cells’ DNA from developing detriments due to environmental factors and normal metabolic processes inside the cell, and try to correct such damage in DNA molecules (Albert et al., 2008). One of these mechanisms is mismatch repair (MMR), which is present in all cells to correct errors that are not otherwise corrected by the proofreading mechanism (Jiricny, 2006). Any functional abnormality of this system results in replication errors that remain uncorrected, leading to a mutator phenotype and sporadic mutation formation. According to the existing information, the association between constitutional mismatch repair deficiencies (CMMRD) and NF1 seems to be incorrect, because some CMMRD patients with rare childhood malignancies have been erroneously included in presumed NF1 cohorts. Therefore, to re-evaluate the likely association between NF1 and childhood malignancies such as central nervous system tumors and rhabdomyosarcomas, all prospective and retrospective studies should be repeated to exclude cases of CMMRD. It should also be pointed out that the incidence of postzygotic NF1 mutations in some CMMRD patients can be responsible for the observed NF1 features (Wimmer, Rosenbaum, & Messiaen, 2017).
Thresholds of adversity and their applicability to endocrine disrupting chemicals
Published in Critical Reviews in Toxicology, 2020
It should be noted that the non-threshold approach adopted for genotoxic carcinogens was developed at a time when modern insights into mechanisms of tumor initiation, promotion and progression and of physiological defense mechanisms were yet to be revealed. First, the body has a wealth of absorption, distribution, metabolism and excretion (ADME) mechanisms in place to detoxify and remove xenobiotic compounds, which reduce the chance of a genotoxic molecule to reach the DNA. Alternatively, metabolic conversion of inactive compounds to toxic derivatives may be increased by enzyme induction; however, enzyme induction typically requires exceeding a threshold concentration in the organism. Secondly, if DNA damage is inflicted, various DNA repair mechanisms are in place to undo the damage, protecting the cell from acquiring DNA mutations. Thirdly, the carcinogenic process is now known to consist of a cascade of cancer-promoting changes, which all need to occur before cancer arises (Cohen et al. 2019; Doe et al. 2019; Wolf et al. 2019). The likelihood that all of these changes occur in concert without being repaired by homeostatic mechanisms is very low, thereby further reducing the chance that exposure to a single genotoxic molecule will lead to cancer, and implying that a biological threshold must exist.
Effect of 900-, 1800-, and 2100-MHz radiofrequency radiation on DNA and oxidative stress in brain
Published in Electromagnetic Biology and Medicine, 2019
Mehmet Esref Alkis, Hakki Murat Bilgin, Veysi Akpolat, Suleyman Dasdag, Korkut Yegin, Mehmet Cihan Yavas, Mehmet Zulkuf Akdag
High-frequency RFR may have a genotoxic effect on tissue (Dogan et al., 2017). Reports up to now on RFR and DNA damage are controversial and the precise mechanism of DNA strand breaks due to RFR is still unknown. Disruptions in DNA spiral can occur due to degradation of DNA repair or damage caused by DNA-DNA and DNA-protein cross-links and/or DNA adduct formation. In addition, RFR can induce the formation of free radicals in brain cells that can cause DNA chain breaks (Deshmuck et al., 2013; Paulraj and Behari, 2007). Single- and double-strand breaks may occur in DNA. Most single-strand breaks can easily be repaired by DNA repair mechanisms. However, it is known that DNA double-strand breaks are very critical for cells and can lead to cell death or apoptosis if not repaired properly (Akdag et al., 2016; Desai et al., 2009). Several techniques have been developed to analyze single and double DNA strand breaks. The most commonly used method is microgel electrophoresis, which is also known as Comet assay or single cell gel electrophoresis (Phillips et al., 2009).