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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
After recognizing the DNA lesion, the monofunctional DNA glycosylase hydrolyzes the N-glycosidic bond at the oxidized bases forming an apurinic/apyrimidinic (AP) site. Two monofunctional glycosylase have been reported in mitochondria till date i.e., uracil-N-glycosylase1 (UNG1) (Anderson and Friedberg 1980) and MutY homolog glycosylase, MUTYH (Ohtsubo et al., 2000). After the action of glycosylase, AP endonuclease (APE1) cleaves the immediate 5ʹ side of the AP site, leaving a 3ʹ-hydroxyl and 5ʹ-deoxyribose-5-phosphate (5ʹ-dRP) residue. The 5ʹ-deoxyribose-5-phosphate residue is then removed by the 5ʹDRP lyase activity of DNA polymerase γ for the subsequent gap-filling polymerization reaction.
DNA Repair During Aging
Published in Alvaro Macieira-Coelho, Molecular Basis of Aging, 2017
This is a repair pathway based on the action of glycosylases. A DNA glycosylase catalyzes the hydrolysis of the N-glycosylic bonds linking bases to the deoxyribose-phosphate backbone, leaving a base-free site (AP site). The removal of such a site requires the action of an AP endonuclease that incises the DNA. Many such enzymes have been characterized in mammals.43 They remove uracil, hypoxanthine, 3-methyladenine, 7-methylguanine, urea, hydroxymethyluracil, and thymine-glycol in different organs of the mouse, rat, calf, and humans. An AP site formed by these enzymes can be removed by the sequential action of a 5′-acting and a 3′-acting AP endonuclease. The resulting gap is enlarged by the action of an exonuclease in both directions that is not specifically repair directed. The gap is filled in by a polymerase and the last nick ligated. Some of these enzymes exhibit both a glycosylase and an AP endonuclease activity, especially those that remove bases damaged by oxidation.
Biomarkers of Toxicant Susceptibility
Published in Anthony P. DeCaprio, Toxicologic Biomarkers, 2006
DNA lesions are of many different types, including single- and doublestrand breaks (induced by X rays), inter- and intrastrand crosslinks (caused by chemical agents, such as the cytostatic cisplatin), and various kinds of base modifications. The consequences of these lesions are at both the cellular level [i.e., cell-cycle arrest, (programmed) cell death, and genomic instability (mutagenesis)] and at the organism level. DNA lesions have been implicated in genetically inherited diseases, carcinogenesis, and aging (27). DNA repair is usually specific for a class of damage; double-strand breaks are repaired by homologous recombination-dependent repair or in an endjoining reaction, and most small base modifications (base damage induced by ionizing radiations and monofunctional alkylating agents) are removed by base excision repair (BER). Nucleotide excision repair (NER) removes primarily bulky adducts, helix-distorting adducts (e.g., BaP, cyclobutane pyrimidine dimers, photoadducts). Mismatches or structural abnormalities at replication forks are repaired by the mismatch repair pathway. However, ample overlap exists in the substrate specificity of repair pathways, and certain proteins are used in more than one pathway (28). NER is one of the major and versatile cellular pathways for the removal of many bulky DNA adducts induced by agents such as UV, cisplatin, and 4-nitroquinoline-1-oxide. In eukaryotes, NER is complex and necessitates the coordinated action of about 20 proteins. NER involves: (i) damage recognition and incision, (ii) excision of damage as part of an oligonucleotide, (iii) repair resynthesis, and (iv) DNA ligation. The BER pathway uses three types of enzymes: (i) DNA glycosylases, which remove modified base(s) from DNA by hydrolysis of the N-glycosidic bond (e.g., 3-methyladenine DNA glycosylase), (ii) AP endonucleases, which excise the abasic sugar and replace it with a correct nucleotide (e.g., Escherichia coli endonuclease III), and (iii) enzymes which have both glycosylase and AP endonuclease activities (e.g., T4 endonuclease V) (29).
Molecular radiobiology and the origins of the base excision repair pathway: an historical perspective
Published in International Journal of Radiation Biology, 2023
The 5′ AP endonucleases not only cleave the DNA back-bone at AP sites but also contain both phosphatase and diesterase activities that are required to remove blocking groups from the 3′ termini of single strand breaks produced directly by ionizing radiation or by the AP lyases present in the glycosylases described above (Demple and Harrison 1994) (Figure 2). Also, as described in the previous Section, the AP endonucleases can initiate the repair of radiation-induced ‘alkali-labile lesions’ or abasic sites which is how they were originally identified (Demple and Harrison 1994). These AP endonucleases cleave on the 5′ side of the abasic site leaving a 3′ hydroxyl and a 5′ deoxyribose bordering the strand break. The AP activities identified in E. coli are exonuclease III (exo III, Xth) (Richardson and Kornberg 1964; Weiss 1976; Gossard and Verly 1978) and endonuclease IV (endo IV, Nfo) (Ljungquist 1977). Unlike endo IV (Ljungquist 1977), the activity of exo III is stimulated by magnesium (Rogers and Weiss 1980) and also contains 3′-5′ exonuclease (Richardson and Kornberg 1964) and RNase H (Rogers and Weiss 1980) activities. Exo III accounts for about 90% of the AP activity in E. coli but the two activities can substitute for one another thus double mutants xth nfo are hypersensitive to the cytotoxic effects of ionizing radiation (Cunningham et al. 1986; Zhang et al. 1992).
Development and implementation of precision therapies targeting base-excision DNA repair in BRCA1-associated tumors
Published in Expert Review of Precision Medicine and Drug Development, 2019
Adel Alblihy, Katia A. Mesquita, Maaz T. Sadiq, Srinivasan Madhusudan
APE1 is upregulated or dysregulated in variable solid cancers such as ovarian, prostate, germ cell tumor and colon cancers. In addition, overexpression or altered levels of AP endonucleases has been demonstrated to increase the resistance of tumor cells to a number of chemotherapeutic agents in several cancers, confirming that APE1 is a critical target for cancer treatment. A large number of APE1 inhibitors have been studied and reviewed in 2012 [104]. E3330 and its analogues have potential clinical therapeutic value as specific inhibitors of the redox activity of APE1, but it does not affect APEI DNA activity [63]. Another APEI inhibitor is CTR0044876, which was the most potent and selective inhibitor, with an IC50 of 3.06 mm. It potentiated the cytotoxicity of TMZ and MMS in HT1080 fibrosarcoma cells. APE1 inhibitors induced synthetic lethality in BRCA2- and ATM-deficient cell lines [75,105]. Qian et al. (2014) showed that the Bcl-2 homology 3 (BH3)-mimetic agent gossypol can bind to the BH3 domain in B-cell lymphoma 2 (Bcl-2) and that Bcl-2 interact directly with the BH domains in APE1. As a result, gossypol inhibits the redox and repair activity of APE1 [106]. Small molecules such as ML199 and its analogues belong to a drug-like was developed to afford compounds that can competitively inhibit APE1 activity [107]. These findings reflect the rapid development and promising results of studies on APE1 inhibitors, which could replace PARPi.
Targeting the DNA damage response in pediatric malignancies
Published in Expert Review of Anticancer Therapy, 2022
Jenna M Gedminas, Theodore W Laetsch
Base excision repair (BER) is utilized by cells to repair small base lesions that do not affect the structure of the helix. These mainly occur due to oxidation, deamination, or alkylation [6]. These lesions usually occur due to spontaneous DNA decay but may also be caused by radiation, cytostatic drugs, or environmental chemicals [6]. Once the base damage is recognized, a damage-specific DNA glycosylase removes the damaged base leaving an abasic site and a 3’-OH is generated at the site of damage by an AP-endonuclease. Finally, DNA polymerase initiates repair synthesis and the nick in the DNA is sealed by a DNA ligase [7].