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Mitochondrial Dysfunction in the Pathophysiology of Alzheimer’s Disease
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
While mitochondria have many antioxidant and DNA repair enzymes including 8-oxoguanine glycosylase 1 (OGG1) and the base excision repair protein MUTYH [34,45,46], the proximity of the mitochondrial genome to the inner mitochondrial membrane where ROS are routinely generated, and lack of protective histone molecules, make them particularly vulnerable to mutations compared to nuclear DNA [47]. mtDNA quality control is crucial for communication with the nucleus. ROS-mediated gene expression elicited by oxidative phosphorylation dysfunction lead to mitochondrial retrograde signaling that stimulates an adaptive nuclear response to mtDNA impairment. Mitochondrial genetic alterations affect the expression of more than 40 nuclear genes [48,49]. Conversely, mtDNA dysfunction can be induced by many signaling molecules that are regulated by nuclear genes, and factors related to mitochondrial metabolism [50–53].
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
An in silico kinetic model of 8-oxo-7,8-dihydro-2-deoxyguanosine and 8-oxo-7,8-dihydroguanosine metabolism from intracellular formation to urinary excretion
Published in Scandinavian Journal of Clinical and Laboratory Investigation, 2021
Anders Jorgensen, Maria Bremholm Thygesen, Uffe Kristiansen, Henrik Enghusen Poulsen
As noted in the methods section, it is important to emphasize that the exact intracellular process underlying urinary 8-oxodG excretion has not been identified. Oxoguanine glycosylase 1 (OGG1), which was initially considered to be the most likely source, excises only the oxidized nucleobase, which is correspondingly found to be reduced in urine of Ogg1−/− knockout mice [25]. Evans et al. recently found no difference in urinary 8-oxodG excretion in genetically modified mice with deficiencies within the nucleotide excision repair system [26]. However, although the intracellular mechanism underlying the urinary excretion of 8-oxodG is unknown, it is still considered that it most likely involves an enzymatic repair process [27]. There is experimental data to support that the Nudix hydrolase NUDT1, which sanitizes the nucleotide pool of 8-oxodG-triphophate (8-oxodGTP), is a candidate enzyme that could ultimately yield free 8-oxodG [28]. Overall, given the threat that damage to DNA or its building blocks constitute to cellular and organismal survival, it would seem unlikely that there is no active (enzymatic) process underlying the release of extracellular 8-oxodG.
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].
Mechanisms of inflammatory responses to radiation and normal tissues toxicity: clinical implications
Published in International Journal of Radiation Biology, 2018
Masoud Najafi, Elahe Motevaseli, Alireza Shirazi, Ghazale Geraily, Abolhasan Rezaeyan, Farzad Norouzi, Saeed Rezapoor, Hamid Abdollahi
Previous studies have reported that mutations in BER genes and defects in MMR repair pathway is associated with chronic inflammation, which can result in incomplete repair of DNA damage, leading to mutation, chromosomal instability, and predisposition to several types of epithelial cancer (Kidane et al. 2014). Chien et al. (2004) have suggested that NO, peroxynitrite, and arsenite can inhibit DNA adduct excision in NER pathway. NO directly affects oxidative DNA damage repair including 8-oxoguanine repair processes. 8-Oxoguanine glycosylase (Ogg1) is responsible for the excision of 8-oxoguanine. An inhibition by NO has been investigated for homologue of Ogg1 protein. This is related to nitrosylation of cysteine residues in the zinc-finger motif of the Ogg1 protein after expose to a NO donor or iNOS-inducing cytokines (Wink and Laval 1994; Jaiswal et al., 2001b). Ogg1 inhibition by NO result in increased accumulation of oxidative DNA lesions (Jaiswal et al. 2001c). The failure to repair 8-oxodG increases mutagenesis and expected to promote cancer initiation and progression. Studies have shown that hOGG1 gene mutations are associated with several human cancers such as lung, kidney, and gastric cancer (Chevillard et al. 1998; Shinmura et al. 1998; Rezapoor et al. 2017).