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Introducing Molecular Biology of Head and Neck Cancer
Published in John C Watkinson, Raymond W Clarke, Terry M Jones, Vinidh Paleri, Nicholas White, Tim Woolford, Head & Neck Surgery Plastic Surgery, 2018
Nikolina Vlatković, Mark T. Boyd
Probably the most significant mutagenic events are those caused by environmental carcinogens, because they affect the most patients and result in cancers with poorer outcomes. The two primary sources of these carcinogens for head and neck cancers are tobacco smoke and alcohol. A critical feature of carcinogenic chemicals is that they often produce chemical modifications, typically of the nucleic acid bases, for which no specific repair pathway exists. This is hardly surprising since the variety of different chemical adducts that smoking alone can cause may exceed one hundred (tobacco smoke contains approximately 50–60 carcinogenic compounds that may display multiple effects on the DNA).33–35 In contrast, the oxidation of one of the DNA bases, guanine, to 8-oxo-guanine by the endogenous production of ROS—one of the most common chemical modifications of DNA to occur—can be repaired by base excision repair (BER) mechanisms initiated by an enzyme that specifically recognizes this common lesion: 8-oxoguanine glycosylase (OGG1).36–38
Introduction to Mitochondria Biology
Published in Sara C. Zapico, Mechanisms Linking Aging, Diseases and Biological Age Estimation, 2017
Christian Thomas, Sara C. Zapico
mtDNA is exposed to more damage than nuclear DNA, accumulating mutations relatively faster than nuclear DNA. This is partly due to the exposure of the mtDNA to ROS, produced as by-products in OXPHOS (Brown et al. 1979, Hashiguchi et al. 2004). However, it has repair mechanisms. The major DNA repair mechanism is BER, encoded by nuclear DNA, although it is present at lower levels in mitochondria (Driggers et al. 1993). BER starts with the recognition of damage, followed by removal of the lesion through enzymatic processes, restoring genomic integrity (Gredilla 2010). There are DNA repair enzymes in the mitochondria such as damage-specific DNA glycosylases, like OGG1, an NTH1, APE and DNA ligase IIIβ. DNA pol γ is implicated in mtDNA BER (Larsen et al. 2005, Szczesny et al. 2003, Lakshmipathy and Campbell 1999). Apart from BER, there is some evidence that mitochondria possess mismatch repair activities, homologous recombination and non-homologous end joining (Mason et al. 2003, Thyagarajan et al. 1996, Coffey et al. 1999).
Novel Developments in Photoprotection: Part I
Published in Henry W. Lim, Herbert Hönigsmann, John L. M. Hawk, Photodermatology, 2007
Besides topical UV protection and radical scavenging, there is a third part of photoprotection strategy that becomes increasingly more important. DNA is constantly damaged and repaired by repair enzymes. The small protein T4 endonuclease V recognizes the major form of DNA damage produced by UVB, which is the cyclobutane pyrimidine (CPD) (12). In a randomized clinical study of the effects of liposomal T4 endonuclease V in patients with xeroderma pigmentosum, the rate of formation of actinic keratoses and basal cell carcinoma was reduced by 68% and 30%, respectively, compared to the control group (13). In another example, people with a polymorphism in the DNA repair gene 8-oxo-guanine glycosylase (OGG1) have an increased risk of skin cancer. Yarosh et al. (14) found that the cells with this variant polymorphism have an increased sensitivity of about 20% to a broad range of cytotoxic agents. The DNA deficits caused by immunosuppressive drugs or the OGG1 polymorphism can be overcome by the delivery of DNA repair enzymes in liposomes. The data suggest that deficits in DNA repair, even if they are not as severe as in the case of XP, may contribute to increased rates of cancer, and that topical therapy with DNA repair enzymes may be a promising avenue for after-sun protection.
Molecular links between COPD and lung cancer: new targets for drug discovery?
Published in Expert Opinion on Therapeutic Targets, 2019
Gaetano Caramori, Paolo Ruggeri, Sharon Mumby, Antonio Ieni, Federica Lo Bello, Vrushali Chaminka, Chantal Donovan, Filippo Andò, Francesco Nucera, Irene Coppolino, Giovanni Tuccari, Philip M. Hansbro, Ian M. Adcock
COPD and lung cancer are both associated with chronic inflammation and oxidative stress. Oxidative stress causes proliferation (lung cancer) and inflammation (COPD) [102]. Mitochondrial damage in COPD patients increases oxidative stress and chronic inflammation increases the risk of carcinogenesis [103]. The former may reflect a shift in the apoptosis/proliferation balance toward hyperproliferation [48] and the transition from normal epithelial to hyperplastic to carcinomatous cells in COPD. Oxidative stress also promotes somatic mutations [80] and affects DNA methylation by forming 8-hydroxy-2ʹ-deoxyguanosine (8-OHdG) residues. ROS and reactive nitrogen species (RNS) also induce single or double-stranded DNA breaks and abnormal DNA cross-linking [104]. The presence of the modified guanine base 7,8-dihydro-8-oxoguanine (8-oxoG) is elevated in the genome of COPD patients. 8-OxoG is primarily recognized by 8-oxoguanine glycosylase 1 (OGG1), which catalyzes the first step in the DNA base excision repair pathway. However, cellular oxidative stress represses the activity of substrate-bound OGG1 enabling NF-κB DNA binding and the enhanced expression of both innate and adaptive immunity. Interestingly, OGG1 is mechanistically linked to oncogenesis via KRAS [105].
Genotoxic impact of long-term cigarette and waterpipe smoking on DNA damage and oxidative stress in healthy subjects
Published in Toxicology Mechanisms and Methods, 2019
Abdulaziz M. Alsaad, Mohammed N. Al-Arifi, Zaid H. Maayah, Ibraheem M. Attafi, Fawaz E. Alanazi, Osamah M. Belali, Ali Alhoshani, Yousif A. Asiri, Hesham M. Korashy
Mechanistically, cancer cells are proposed to appear through the accumulation of genetic modulations that confer survival and dysregulation of DNA repair genes leading to genome instability and development of cancers (de Boer and Hoeijmakers 2000; Beyersmann and Hartwig 2008; Helleday et al. 2008; Curtin 2012). Several reports showed that polymorphisms in genes like OGG1 and XRCC1 have been linked to cancer (Wilson et al. 2011). These genes are also found dysregulated in various cancers (Wilson et al. 2011). For example, OGG1, which repairs the damaged guanine bases, was reported to be involved in tumorigenesis (Arai et al. 1997; Chevillard et al. 1998; Shinmura and Yokota 2001). Collectively, the induction of oxidized DNA adduct 8-OHdG and inhibition of DNA repair genes (OGG1 and XRCC1) illustrates the consequence of DNA damage on genotoxicity and carcinogenicity of cigarette and waterpipe smoke.
Oxidative stress, antioxidant capacity, biomolecule damage, and inflammation symptoms of sickle cell disease in children
Published in Hematology, 2019
Sebaranjan Biswal, Huma Rizwan, Sweta Pal, Silpa Sabnam, Preetinanda Parida, Arttatrana Pal
In SCD subjects, sickle hemoglobin polymerization leads to a remarkable spectrum of biochemical, molecular, and physiological pathology associated with many clinical complications. Here, we observed that the level of LPO and PC was significantly (p < 0.001) increased in SCD children as compared to healthy individuals (Figure 2(A&B)). Also, the total thiol level was significantly (p < 0.001) higher in children with SCD as compared to healthy individuals (Figure 2(C)). OGG1 is known as the DNA repair enzyme, hence acts as an important DNA damage sensor. Figure 2(D) shows that the expression of OGG1 at mRNA level was decreasing in SCD children as compared to healthy ones. Again, we checked the OGG1 expression at the protein level and found the same pattern of results as in the case of mRNA expression in SCD children (Figure 2(E)). Similarly, H2A.X is another DNA damage marker. As shown in Figure 2(E), the expression of H2A.X was increased in SCD children as compared to the healthy one.