DNA Repair During Aging
Alvaro Macieira-Coelho in 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.
Mitochondrial Genome Damage, Dysfunction and Repair
Shamim I. Ahmad in Handbook of Mitochondrial Dysfunction, 2019
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.
Mutagenic Consequences Of Chemical Reaction with DNA
Philip L. Grover in Chemical Carcinogens and DNA, 2019
The right-hand side of Figure 1 shows a more recently discovered variation in which the damaged base is recognized by an N-glycosidase which removes the base, leaving an apurinic (or apyrimidinic) site. Although such sites are alkali-labile and show up as discontinuities in alkaline sucrose gradients, the DNA backbone is intact in vivo. Apurinic sites, which can also form spontaneously, are recognized by an apurinic endonuclease, and the subsequent stages of repair are presumably identical to those of classical excision.18
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].
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.