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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
Nucleotide excision involves an initial attack on the polynucleotide backbone; base excision repair does not. There exist three major subdivisions of this repair scheme. Alkylation damage and, in particular, O6-alkylguanine products (see Section II.A.4) may be repaired by direct dealkylation through transfer of the alkyl group to an acceptor protein, which converts the DNA to its original unaffected form. This repair cannot be measured by unscheduled DNA synthesis (UDS, see Section II.B.1) or by repair replication. A second base excision repair pathway involves the removal of the affected base itself without touching the polynucleotide strand. By one pathway a new base is inserted in place of the old one, while by another there is an endonuclease attack on the AP site, as already described.
Exercise, Metabolism and Oxidative Stress in the Epigenetic Landscape
Published in James N. Cobley, Gareth W. Davison, Oxidative Eustress in Exercise Physiology, 2022
Gareth W. Davison, Colum P. Walsh
Our laboratory has consistently demonstrated that high-intensity exercise leads to guanine nucleotide oxidation (Fogarty et al., 2013) and DNA single- and double-strand breaks; the latter quantified using a marker of histone phosphorylation, γ-H2AX combined with 53BP1 (Williamson and Davison, 2020). Other work by Williamson et al. (2020) shows that high-intensity (95% heart rate max) exercise increases nuclear (single-cell gel electrophoresis comet assay) and mitochondrial DNA damage (Long Amplicon-Quantitative Polymerase Chain Reaction, LA-qPCR assay) across lymphocytes and muscle respectively. DNA bases are directly modified by ROS, where the hydroxyl free radical () can play an integral role through its production by Fenton reactions that involve the reduction of H2O2 by either ferrous (k ~ 76 M−1 s−1) or copper ions (k ~ 4.7 × 103 M−1 s−1) (Davison et al., 2016, 2021). -mediated DNA changes are initiated by hydrogen abstraction or by interfering with a DNA base (Davison, 2016); an example being the oxidation of 5mC to 5hmC leading to demethylation at CpG sites (Madugundu et al., 2014; Dimauro et al., 2020; Figure 17.3). While not shown in an exercise context per se, ROS-induced DNA damage may interfere with epigenetic processes. production can directly modify DNA methylation through oxidation of guanosine to 8-oxo-2′-deoxyguanosine (8-oxodG). 8-OxodG in normal cells represents ~1 in 106 guanines, but this can increase by an order of magnitude under conditions of oxidative stress (Fleming and Burrows, 2020a), with an increased steady-state level of 8-oxodG lesions leading to stalled replication forks and C:G to A:T transverse mutations (van Loon et al., 2010). Usually, 8-oxodG is recognised and removed from an OG:C base pair in duplex DNA by 8-oxoguanine DNA glycosylase (OGG1) through cleavage of the glycosidic bond between the ribose and the base, releasing 8-oxodG and generating an apurinic (AP) site in DNA. This short-patch base excision repair (BER) mechanism further involves AP site cleavage by AP-endonuclease-1 (APE1) to re-synthesise undamaged DNA using the cytosine base opposite as a template for insertion of an undamaged G nucleotide (Fleming and Burrows, 2020a). However, on 8-oxodG accumulation, methylation of adjacent cytosines is attenuated, leading to a state of hypomethylation and transcriptional activation (Le and Fujimori, 2012). Zhou et al. (2016) postulate that OGG1 promotes DNA demethylation by recruitment of TET1 to the oxidised lesion, thus suggesting a model in which oxidative stress recruits OGG1/TET1 complex proteins to 8-oxodG, facilitating the conversion of 5mC through to 5caC close to sites of ROS-induced damage. However, apart from thee reports there is currently not a great deal of additional evidence of APE1 or OGG1 being linked to DNA demethylation in a wider context.
Therapeutic Perspective of Temozolomide Resistance in Glioblastoma Treatment
Published in Cancer Investigation, 2021
Qin Xia, Liqun Liu, Yang Li, Pei Zhang, Da Han, Lei Dong
In malignant tumors, the BER system is hyperactive and negatively regulates the MMR system, which contributes to drug resistance. The BER system rapidly recognizes and repairs N-methylated bases, which cannot be recognized by MGMT, and the BER system corrects mispairs recognized by MMR. N-methylpurine DNA glycosylase (MPG) excises DNA alkylated bases in the BER system, and it creates an apurinic/apyrimidinic site (AP-site). The corresponding DNA glycosylase and/or apurinic/apyrimidinic endonuclease (APEX1) will hydrolyze the 5′ (backbone) at the AP-site and ultimately lead to single-strand breaks. Agnihotri et al. built a GSC-like system using GB xenograft models and demonstrated that MPG expression enhanced TMZ resistance compared with cell lines that did not express MPG (31). Therefore, MPG loss increases the sensitivity to TMZ. In addition, poly ADP-ribose polymerase (PARP), which is upregulated in gliomas, repairs DNA single-strand breaks and regulates the BER and MMR pathways (32). Bandey et al. showed that granulin (GRN) precursor upregulated DNA repair (like PARP) and orchestrated tumor stemness to promote TMZ resistance in GB (33). A study by Tentori et al. found that in eight out of ten GSC lines, the combination of PARP1 inhibitors with TMZ increased the anti-tumor effect (34). Besides, non-homologous end joining (NHEJ) and homologous recombination (HR) repair double-strand break indirectly induced by TMZ and likely contribute to chemoresistance in GB (35).
Unfolding the Role of Splicing Factors and RNA Debranching in AID Mediated Antibody Diversification
Published in International Reviews of Immunology, 2021
Ankit Jaiswal, Amit Kumar Singh, Anubhav Tamrakar, Prashant Kodgire
SHM takes place in the variable regions of Ig light and heavy chain in B-cell, upon antigenic stimulation [6]. SHM introduces point mutation in the variable region of Ig genes which produces a high as well as a low-affinity antibody. Further, B-cells expressing high-affinity antibody expands into plasma B-cell and memory B-cell, whereas apoptosis of B-cells expressing low affinity takes place. SHM together with clonal selection is known as affinity maturation [7]. SHM takes place in the dark zone (DZ) of the germinal center. Subsequently, SHM generated antibody moves to the light zone (LZ) of the germinal center where the clonal selection of high-affinity antibody and CSR takes place. SHM is mediated by genome mutator enzyme AID, that induced a point mutation via deamination of cytosine (C) into uracil (U), C to U conversion leads to the creation of a mismatch that can have various fates inside the B-cell [8]. If a U:G mismatch is unrepaired, and replication occurs then it leads to the creation of a transition mutation from C to T [9]. Moreover, if Uracil DNA glycosylase (UNG) recognize U:G mismatch, it removes uracil base, leads to the creation of abasic site (AP) [10]. In the context of Ig genes, AP site is repaired by the recruitment of error-prone DNA polymerase results in a mutation. Additionally, if U:G mismatch is processed by base excision repair (BER) or mismatch repair system (MER) results in insertion, deletion as well as substitution mutation [11] (Figure 1A). Thus, AID initiated mutations in Ig genes are unfaithfully repaired that result in SHM.
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
Apurinic/apyrimidinic endonuclease 1 (APE1) immediately incises the DNA backbone to the AP site, creating a nick bordered by the 5′- deoxyribose phosphate and 3′- hydroxyl groups. Such groups preform as blocking moieties requiring further support from subsequent BER enzymes such as DNA polymerase β (Pol β) and λ and polynucleotide kinase 3ʹ-phosphatases (PNKP). In the BER-short-patch pathway (SP-BER), Pol β incorporates a single nucleotide into the processed AP site. High ATP concentrations are required to complete this mechanism. However, if the ATP concentration is low or if the oxidative state of abasic lesions is changed, repair proceeds via the long patch pathway (LP-BER) are completed [65]. This pathway incorporates multiple nucleotides (usually 2–7) by proliferating cellular nuclear antigen (PCNA)-dependent polymerases such as POLɛ and δ or alternatively, a Polβ/Rad9-Rad1-Hus1 complex, which has the same structure as PCNA. The existing 5′-end in the BER-Long-patch pathway (LP-BER) is displaced by Flap endonuclease 1 (FEN1) and DNA ligase 1 seals the DNA strand break, completing the LP-BER. In the SP-BER, this primarily occurs via DNA ligase III-XRCC1 (X-ray cross-complementation group I) [66,67].