DNA repair systems

DNA repair Because most mutations are very damaging, even the simplest organisms have enzyme systems that repair DNA. These DNA repair systems are important because genetic defects in them can cause some human diseases. 

Although cadmium is not strongly mutagenic, it is known that it causes increased oxidative DNA damage and that it inhibits the DNA repair systems. It has also been found to induce cell death both by necrosis and apoptosis. Since the latter is extremely calcium-dependent, it seems likely that the pro-apoptotic effects of cadmium are due to its interference with calcium homeostasis. 

An in-depth study of DNA repair systems (Aravind et al., 1999a) has concluded that few, if any, repair proteins occur with identical collinear domain arrangements in all three kingdoms of life. Approximately 10 enzyme families of adenosine triphosphatases (ATPases), photolyases, helicases, and nucleases were identified that are all likely to have been present in the cenancestor. These enzymatic domains are accompanied in DNA repair proteins by numerous regulatory domains. This indicates that the domain architectures of these proteins are labile, with incremental addition and/or subtraction of domains to conserved cores to be a common phenomenon except in the most closely related species. 

The SOS response is an inducible DNA-repair system that allows bacteria to survive rapid increases in DNA damage. Two proteins play a key role in... 

The body s natural defenses against overenthusiastic oxidation include a-lipoic acid, reduced glutathione, ascorbic acid, the tocopherols, the carotenoids, and a number of enzymes such as epoxide hydrolase and the like. Very efficient DNA repair systems also operate defensively. These various means are remarkably effective, but DNA assault is continuous, cumulative, and implacable. Thus, many degenerative diseases are associated with aging because of the gradual slippage in functional fidelity of cellular machinery which occurs with age. 

The nature of the difference in response to Pt-chemotherapy between tumor and normal cells is still unknown. It is possible that rapidly dividing (tumor) cells are more susceptible because of the inhibitory effect of Pt-DNA adducts during the DNA replication, a prerequisite for cell division. Another explanation may be a difference in the capacities of the various cell types to remove Pt-DNA adducts. The influence of DNA repair systems on the survival of cisplatin-treated cells has clearly been demonstrated in... 

Aside from the expression of histidine mutations that are easily detected, other properties have been built into the Salmonella strains by mutation to increase their sensitivity. The strains cure defective in DNA excision repair (uvrB). In this case, the increased sensitivity probably is due to the failure to remove some DNA adducts that could lead to mutation. The strains also possess a mutation (rfa) that removes part of the lipopolysaccharide barrier of the bacterial cell wall and thereby makes the cells more permeable to some chemicals. Finally, Salmonella strains TA98 and TA100 contain the R-factor plasmid pkMIOl,277 which increases sensitivity probably by increasing the activity of an error-prone DNA-repair system. 

The rare human genetic disease xeroderma pigmentosum is due to a deficiency in one of the many components of the DNA repair system. Exposure to ultraviolet light causes skin tumors. Individuals with this disease are so sensitive to ultraviolet light that they must avoid even household fluorescent lamps. 

The third aspect is the high error rate and lack of efficient DNA repair systems, leading to a high mutation rate for mtDNA. It is estimated that mtDNA is 7-17 times more prone to mutation than somatic DNA. These aspects of mitochondrial biogenesis lead to the production of mutant mtDNA, contributing to the overall degree of heteroplasmy in human tissues. 

Whilst cells are normally equipped with extensive DNA repair systems these can sometimes become overwhelmed, or they may be defective for genetic reasons. Patients with genetic defects in their DNA repair systems (e.g. Xeroderma pigmentosum, Fanconi s syndrome, Bloom s syndrome) are predisposed to the development of cancer [132]. 

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