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Mitochondrial Genome Damage, Dysfunction and Repair
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Kalyan Mahapatra, Sayanti De, Sujit Roy
The sophisticated antioxidant system of mitochondrial matrix restricts the steady-state concentration of O2‒• within 10–10 M (Cadenas and Davies, 2000). The free radicals escaping from this detoxification process can cause oxidative damage to various biological components. But because mitochondrial DNA is in close proximity to the mitochondrial respiratory chain, it is very much susceptible to oxidative damage by various free radicals. The high rate of oxidative stress operating within the mitochondrial matrix causes a broad spectrum of mitochondrial DNA damage including modifications to bases such as 8-oxo-2′-deoxyguanosine (8-oxodG), 8,5′-cyclo-2′deoxynucleosides, thymine glycol, 5,6-dihydroxycytosine, 2,6-diamino-4-hydroxy-5-formamidopyrimidine. Along with this sugar break down products (such as 2-deoxypentose-4-ulose, 2-deoxypentonic acid lactones and erythrose), base free sites or abasic sites, strand breaks and chemical adducts of bases such as aldehyde modifications are also the consequences of the oxidative stress.
Melatonin: A “Guardian” of the Genome and Cellular Integrity for Prevention of Photocarcinogenesis
Published in Andreia Ascenso, Sandra Simões, Helena Ribeiro, Carrier-Mediated Dermal Delivery, 2017
Patricia Manteigas, Andreia Ascenso
Two typical DNA lesions arise from the interaction of ROS with this molecule [105]. The first comes from the oxidation of the Guanine (G) base resulting in 8-oxo-7,8-dihydroguanine (8-oxo-dG) and 8-hydroxy-2-deoxyguanosine (8-OH-dG) [119,120]. The second is represented by the formation of 2,6-diamino- 4-hydroxy-5-formamidopyrimidine (FapydG), which is the most predominant guanine-derived modification under hypoxic conditions [118]. In addition, other base alterations can occur. The production of substances like 5,6-dihydroxy-5,6 dihydrothymine (thymine glycol) and 5,6-dihydroxy-5,6-dihydrocytosine (cytosine glycol) is the result of the reaction between OH and pyrimidine bases [118]. It should be mentioned that thymine glycol and 8-oxo-dG are known to be markers of oxidative stress in carcinogenesis process [118]. The base excision repair (BER) is another repair mechanism of lesions that result from exposure to endogenous or exogenous ROS avoiding the accumulation of unrepaired 8-oxo-dG and 8-OH-dG photoproducts [121,122]. Besides ROS, RNS are also able to induce DNA lesions [120]. The increment of nitric oxide (NO) levels can be due to UV-induced up regulation of NO synthetases and to UVA decomposition of endogenous NO sources. Nitrotyrosine and 8-nitroguanine are two species resulting from the interaction between RNS and proteins or DNA, respectively [120]. The last interaction occurs commonly with Guanine, once it has the lowest oxidation potential being the most susceptible base [102]. The genotoxicity process is represented in Fig. 2.5.
The Molecular and Genetic Effects of Ultraviolet Radiation Exposure on Skin Cells
Published in Henry W. Lim, Herbert Hönigsmann, John L. M. Hawk, Photodermatology, 2007
Marjan Garmyn, Daniel B. Yarosh
Aside from these direct effects of UVR, DNA damage can form by indirect effects, particularly from oxidation. UVR absorbed by as yet poorly defined chromophores in skin can generate oxygen radicals that react with DNA. The most vulnerable place in DNA is oxidation of the 8 position of guanine, yielding 8-oxo-guanine (8oG). Another detectable oxidized base is the thymine glycol. UVA, which produces relatively more oxidation damage than photoproducts when compared with UVB, still produces three to six times more CPD than 8oG in DNA (2). Single- or double-stranded breaks are uncommon events resulting from UVR.
Molecular radiobiology and the origins of the base excision repair pathway: an historical perspective
Published in International Journal of Radiation Biology, 2023
At the DNA Repair meeting in 1974, there were a number of research efforts presented that were related to ionizing radiation damage to DNA and its cellular consequences. Cerutti’s lab had shown that a radiolysis product of thymine, probably thymine glycol, appeared in the acid soluble fraction during post-irradiation incubation of Micrococcus radiodurans (Hariharan and Cerutti 1972) and after osmium tetroxide treatment (Hariharan et al. 1975). They also observed a similar activity in E. coli, HeLa and Chinese hamster ovary cells (Hariharan et al. 1975). However, they did not establish whether it was selective excision of a damaged base or just post-irradiation degradation. Setlow’s laboratory found an endonuclease activity in Micrococcus luteus that cleaved DNA irradiated in vivo and in vitro by 1972; Setlow and Carrier 1973) and Wilkins showed that E. coli DNA was also sensitive to this activity (Wilkins 1973a, 1973b). Similar activities were identified by Kada in Bacillus subtilis (Noguti and Kada 1975a, 1975b) and by Brent in HeLa cells (Brent 1973).
Consequences and repair of radiation-induced DNA damage: fifty years of fun questions and answers
Published in International Journal of Radiation Biology, 2022
Of course, we initially started our individual lesion consequences studies with thymine glycol, which unlike most base lesions with an intact ring, is a block to replicative and repair DNA polymerases. We had predicted and our molecular modeling had predicted that the methyl group on the C5 position would collide with the 5′ base in the template strand stopping primer extension. So, it was quite a thrill after all these years when Pierre Aller, a post-doc in Sylvie’s lab, solved the structure of replicative polymerase RB69 with Tg in the active site and showed that our prediction was correct. The templating Tg is intrahelical and forms a correct base pair with the incorporated A. But, the C5 methyl group protrudes axially from Tg and hinders stacking of the adjacent template base so that the next nucleotide cannot be incorporated into the growing primer strand (Figure 4) (Aller et al. 2007, 2011).
Chemistry of ROS-mediated oxidation to the guanine base in DNA and its biological consequences
Published in International Journal of Radiation Biology, 2022
Aaron M. Fleming, Cynthia J. Burrows
An argument for a significant role played by the hydantoins in cellular oxidative damage is the fact that they are by far the best substrates known for the NEIL repair enzymes (Krishnamurthy et al. 2008; Liu et al. 2010; Fleming and Burrows 2017a). Sheila David’s laboratory (UC-Davis) has shown that NEIL1, the human homolog of bacterial endonuclease VIII, recognizes and excises hydantoin bases with a strong preference over their originally discovered substrates such as thymine glycol, although the substrate specificity is dependent on native vs. edited versions of the glycosylase (Yeo et al. 2010). The hydantoins Sp and Gh are found to arise from endogenous oxidative stress whereas 2Ih can also be formed from radiation damage (Fleming and Burrows 2013; Alshykhly et al. 2015b). Thymine glycol (Tg) on the other hand is a product principally of radiation damage and metabolism because of the generation of the highly reactive hydroxyl radical which can hydroxylate any base (Cadet et al. 2008). It is fitting therefore that edited NEIL1, which is expected to increase during inflammation creating endogenous carbonate radical anion, has a heightened substrate preference for Sp and Gh compared to Tg.