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Review

The Link Between Human Alkyladenine DNA Glycosylase and Cancer Development

by
Olga A. Kladova
* and
Aleksandra A. Kuznetsova
*
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(15), 7647; https://doi.org/10.3390/ijms26157647
Submission received: 27 June 2025 / Revised: 4 August 2025 / Accepted: 5 August 2025 / Published: 7 August 2025
(This article belongs to the Special Issue Editorial Board Members’ Collection Series: Genome Stability)
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Abstract

Alkyladenine DNA glycosylase (AAG) is a critical enzyme in the base excision repair (BER) pathway, responsible for removing a broad spectrum of alkylated DNA lesions. While AAG maintains genomic stability, dysregulated activity has been implicated in cancer development, drug resistance, and neurodegenerative diseases. This review synthesizes the current knowledge on AAG’s structure, catalytic mechanism, and polymorphic variants, highlighting their potential roles in disease pathogenesis. A comprehensive bioinformatics analysis of over 370 AAG single-nucleotide polymorphisms (SNPs) is presented, identifying ~40% as high-risk variants likely to impair enzymatic function. Notably, 151 SNPs were predicted to be damaging by multiple algorithms, including substitutions at catalytic residues and non-conserved sites with unknown functional consequences. Analysis of cancer databases (COSMIC, cBioPortal, NCBI) revealed 93 tumor-associated AAG variants, with 18 classified as high-impact mutations. This work underscores the need for mechanistic studies of AAG variants using structural biology, cellular models, and clinical correlation analyses. Deciphering AAG’s polymorphic landscape may unlock personalized strategies for cancer prevention and treatment.

1. Introduction

The influence of various environmental factors leads to the damage of cellular DNA. The resulting DNA lesions can lead to the occurrence of mutations in the genome and, as a consequence, to the disruption of the genomic integrity. To preserve the stability of the genome in living organisms, there are several mechanisms of DNA repair [1,2,3,4,5]. The base excision repair (BER) pathway is responsible for removing non-bulky DNA lesions; it is an elaborate system that repairs a wide range of damaged heterocyclic DNA bases [6,7,8,9,10]. The first participants in this process are DNA glycosylases, which identify, recognize and remove the damaged DNA base [11,12,13,14,15,16,17,18,19,20]. The resulting apurinic/apyrimidinic site (AP site) can then be hydrolyzed by the human AP endonuclease 1 (APE1) [21]. The next step involves DNA polymerase β (Polβ), whose main function is to fill the gap formed in DNA after the action of DNA glycosylases and APE1 [22,23,24]. The final step in repairing the original DNA sequence is the ligation of the single-strand break by DNA ligase I or the XRCC1/LigIII complex [25,26,27,28,29,30].
Alkylated DNA lesions can arise from both endogenous sources (such as S-adenosylmethionine) and exogenous agents such as environmental toxins or anticancer chemotherapy drugs [31,32]. Most alkylating drugs are methylating agents that form adducts at the N and O atoms in heterocyclic bases. These lesions are toxic for cells because they can block DNA replication [33]. The repair of DNA lesions caused by alkylating agents is efficiently performed by the BER pathway. Alkyladenine DNA glycosylase AAG (also called methylpurine DNA glycosylase MPG, or ANPG) is the major BER enzyme that recognizes and removes a wide range of modified alkylated DNA heterocyclic bases [32,34]. This DNA glycosylase is a monofunctional enzyme and hydrolyzes the N-glycosidic bond of the lesion containing nucleotide, resulting in the formation of an AP site, which is also cytotoxic and mutagenic [35,36]. Changes in AAG activity due to the expression of functionally deficient enzyme variants can lead to the accumulation of unrepaired DNA damage. One of the reasons for the expression of enzyme variants with altered properties may be the consequence of the substitution of a single nucleotide in the gene encoding the protein—single-nucleotide polymorphisms (SNP). It is currently known that natural SNPs are widespread in the human population, and variants of DNA repair enzymes are often associated with the occurrence of gene-associated diseases [37,38,39]. In this paper, we analyzed the possible influence of natural SNPs on the structure and functions of AAG. Based on the analysis, we identified the AAG polymorphic variants that have a high potential to negatively affect the enzyme’s functioning. SNPs in DNA repair enzymes like AAG are critical to study for several reasons, spanning fundamental biology, disease mechanisms, and clinical applications. SNPs in AAG may impair DNA repair, leading to accumulation of mutagenic lesions and genomic instability—a hallmark of cancer. The impaired repair of oxidative lesions due to AAG SNPs could contribute to neuronal damage, similar to 8-oxoguanine DNA glycosylase (OGG1) variants in Alzheimer’s disease [40]. The interindividual variability in disease could be correlated with AAG polymorphisms activity and could explain why some individuals develop cancers despite similar exposures to, for instance, tobacco carcinogens. Moreover, AAG activity can influence chemosensitivity. Tumors with hyperactive variants may resist alkylating agents, while hypoactive variants could enhance drug efficacy. SNPs in AAG can be functional modifiers of DNA repair capacity with direct links to disease etiology, therapy response, and population health. Decoding AAG SNPs is a gateway to personalized cancer prevention, targeted therapies, and a deeper understanding of genomic instability.

2. Structure and Catalytic Mechanism of AAG

DNA glycosylases specific for alkylated DNA lesions have been found in all living organisms from archaea and bacteria to higher eukaryotes. The structural arrangement of alkylpurine DNA glycosylases allows these enzymes to be divided into three structural families: the AAG family, including human alkyladenine DNA glycosylase, the ALK family, including prokaryotic DNA glycosylases AlkC and AlkD, and the HhH-GPD family, containing all other alkyladenine DNA glycosylases [41,42,43,44]. Notably, AAG lacks the helix–hairpin–helix DNA-binding motif that is characteristic of many DNA glycosylases. Thus, AAG and other homologous mammalian alkyladenine DNA glycosylases belong to a separate structural group [44,45,46,47]. Despite the different architecture, AAG and the HhH-GPD family enzymes have structurally similar active sites containing functionally homologous amino acid residues interacting with the everted nitrogenous base, whereas enzymes of the ALK family differ significantly both in structure and in the mechanism of damage recognition [48].
The AAG is a monosubunit protein consisting of 298 amino acid residues and possessing a mixed α/β structure (Figure 1). The mpg gene encoding human AAG is located on the short arm of chromosome 16 and consists of five exons, two of which (1a and 1b) are localized in the promoter region. As a result of post-transcriptional modification, several AAG isoforms with different transcript lengths can be formed [49,50,51].
AAG contains an extended unstructured N-terminus, the role of which remains unclear to this day. This enzyme region may potentially participate in interactions with other proteins. For example, it was shown that AAG participates in a complex with actively transcribing RNA polymerase II [52], probably due to the direct interaction of the unstructured N-terminal region of AAG with the ELP1 subunit of the Elongator transcription complex.
The AAG enzyme belongs to the class of hydrolases and the hydrolysis of the N-glycosidic bond of the damaged heterocyclic base occurs through the activation of a water molecule. The amino acid residue Glu125 deprotonates a water molecule, which then attacks the C1′ atom of deoxyribose, followed by damaged base release. The amino acid residue Arg182 also participates in the coordination of the water molecule. The amino acid residues Tyr127 and Tyr159 contribute to the correct orientation of the damaged nucleotide in the enzyme active site. While Tyr127 forms a stacking interaction with the base plane, the Tyr159 is oriented perpendicular to it [44].
Human AAG is responsible for the recognition and removal of alkylated purine bases such as 3-methyladenine, 7-methylguanine, or 1,N6-ethenoadenine (Figure 2). 7-Methylguanine comprises more than 70% of the total alkylated products following treatment of DNA with monofunctional methylating agents, while 3-methyladenine accounts for about 10% [53,54]. Although 7-methylguanine itself is not cytotoxic or mutagenic, it can undergo spontaneous depurination with the formation of toxic and mutagenic AP sites. In contrast, 3-methyladenine can block replication [55]. 1,N6-ethenoadenine is an endogenous DNA lesion formed during the action of lipid peroxidation products and aldehydes on DNA [56,57]. AAG is also capable of removing the hypoxanthine residues from DNA, formed as a result of oxidative deamination of adenosine [58,59], as well as removing oxanine residues from double-stranded and single-stranded DNA, formed as a result of guanosine oxidation [60]. Thus, AAG has broad substrate specificity [49], and a decrease in its activity can lead to the formation of unrepaired alkylated/oxidized DNA bases.
It should be noted that the full-length AAG has different catalytic activity compared to the truncated enzyme lacking the unstructured N-terminal tail, which is most often used in experimental studies. For example, the full-length enzyme can cleave single-stranded DNA containing a uridine residue [56]. The presence of the unstructured N-terminal tail of AAG in cells apparently modulates the enzyme activity. It has also been shown that unlike the truncated enzyme, wild-type AAG does not cleave DNA substrates containing 1-methyladenine, 3-methylthymine, 3-methylcytosine, 3-methyluracil, 3-ethyluracil, and 3,N4-ethenocytosine. However, AAG can still bind the lesions that cannot be removed, which leads to unproductive binding [56]. On the one hand, such unproductive binding can inhibit the repair of these lesions by direct oxidative demethylation enzymes [61]; on the other hand, it can interfere with the interaction of AAG with its own substrates [62].

3. Polymorphic Variants of AAG and Other DNA Repair Enzymes

To date, a large number of studies have demonstrated the link between the occurrence of cancer and neurodegenerative diseases and the expression of mutant variants of DNA repair enzymes. One mechanism by which such mutant variants can arise is through single-nucleotide substitutions, also called single-nucleotide polymorphisms (SNPs). The prevalence of SNPs and resulting amino acid substitutions in base excision repair enzymes is widespread in the human population [63,64,65]. For many polymorphic variants of enzymes, their altered activity and association with cancer and neurodegenerative diseases have been demonstrated [66]. Studies showed that the polymorphic variant of DNA polymerase β (Polβ) Lys167Ile was found in patients with esophageal carcinoma [67]. It was shown that Lys167Ile amino acid substitution significantly reduces enzyme activity. The polymorphic variant of Polβ Glu288Lys is shown to be associated with rectal cancer, and this mutant form increased the mutation frequency threefold compared to the wild-type enzyme [68]. Polymorphic variants of OGG1 Ala53Thr and Ala288Val have reduced enzymatic activity and were found in patients with Alzheimer’s disease [40]. The low-activity variant of DNA glycosylase NEIL1 Gly83Asp has been associated with an increased risk of cancer [69]. The polymorphic variant of AP endonuclease 1 (APE1) Asp148Glu has been associated with the development of breast cancer, gastrointestinal tract cancer and a moderate risk of lung cancer [70,71,72]. Another polymorphic variant of APE1, Arg237Cys, which has reduced AP-lyase and exonuclease activity, has been associated with amyotrophic lateral sclerosis [73]. The relationship between polymorphisms of genes encoding BER proteins and the etiology of some human diseases remains an open and attractive area for research.
Despite extensive data on polymorphic variants of other DNA repair enzymes, similar studies of AAG mutations are lacking. Several SNPs of the AAG enzyme have been identified in human populations through genetic analysis, but for most variants, their clinical and functional significance remains unclear. Adhikari et al. has characterized polymorphic variants of AAG containing amino acid substitutions at positions K22Q, P64L, Y71H, Q93R, R120C, R141Q, A258V and A298S [74]. These studies showed a neutral effect for mutant variants K22Q, P64L, Y71H, Q93R, A258V and A298S, with enzymatic activity toward hypoxanthine and 1,N6-ethenoadenine containing DNA similar to that of wild-type AAG. Interestingly, the polymorphic variants R120C and R141Q showed decreased activity compared to the wild-type enzyme. Mouse embryonic fibroblast (MEF) cells expressing these AAG mutants also showed increased levels of unrepaired DNA bases. For the intron variant of the mpg gene rs2858056, an association with rheumatoid arthritis risk was demonstrated [75,76]. Thus, the functional characterization of natural polymorphic variants of AAG remains an area requiring more detailed analysis.
Giving the limited data on the enzymatic activity of polymorphic variants of the AAG enzyme, this work presents a systematic study of AAG mutants to characterize the possible consequences of amino acid substitutions in this enzyme.

4. Analysis of SNP Variants of AAG

There are many bioinformatic approaches that currently allow for prediction of the effect of SNP on protein function. This paper focuses on the analysis of known AAG natural polymorphisms from the NCBI dbSNP database (http://www.ncbi.nlm.nih.gov/snp, accessed on 1 February 2025) to evaluate the possible effects of SNPs on its functions. According to the NCBI dbSNP database, the mpg gene contains more than 4600 different single-nucleotide substitutions, a significant proportion of which are located in non-coding intron regions. SNPs leading to a change in the class of amino acid residue (non-synonymous or missense mutations) located in the coding exon region were selected. SNPs resulting in amino acid substitutions were analyzed using six software applications: SIFT (sorting intolerant from tolerant [77,78]), PolyPhen-2 (polymorphism phenotyping v.2 [79,80]), CADD (combined annotation dependent depletion [81,82]), Mutation taster [83,84], MetaRNN [85] and Provean (protein variation effect analyzer [86,87]) to identify the possible influence on enzyme activity. The applications use different algorithms for predicting the possible impact of amino acid substitutions and, thus, using several applications allowed us to increase the accuracy of the predictions and obtain a ranked list of SNPs. Analysis using only one predictive approach may be insufficient since SNPs with predictions near threshold values may be erroneously classified. Also, it should be emphasized that using only a prognostic approach to describe the impact of SNPs is not enough. Experimental verification is necessary to confirm the results obtained using bioinformatic methods.
SNPs were classified as follows (Table S1):
  • High negative impact: negative prediction in ≥5 of 6 programs.
  • Medium impact: negative prediction in 3–4 programs.
  • Low impact: negative prediction in ≤2 programs.
The prediction programs rely on X-ray structural data, protein sequence homology, and physical properties of amino acid residues; so, the results obtained for amino acid residues located in the unstructured N-terminus may not accurately reflect the actual impact of the SNP.
After screening, 151 polymorphic variants were predicted to have damaging effects in at least five of the six programs used. The selected amino acid substitutions were distributed throughout the protein sequence, except in the unstructured N-terminal region. This approach also identified substitutions of functionally significant amino acid residues, including catalytically important Glu125Lys, Tyr127Cys and Tyr159Ser. For the polymorphic variants Arg120Cys and Arg141Gln, which were previously characterized [74], analysis revealed an average probability of a detrimental effect on the enzyme function based on predictions from 4 of 6 and 3 of 6 programs, respectively. For the mutant forms K22Q, P64L, Y71H, Q93R, A258V and A298S, the predicted effect was neutral, consistent with previous findings showing comparable activity to that of wild-type AAG [74]. However, most of the selected polymorphic variants do not involve catalytically significant amino acid residues, and, consequently, their functional significance remains unclear.

5. The Role of AAG in the Development of Oncological Diseases

The role of DNA repair enzymes in the development of cancer is still an active area for scientific research [66,88]. Increased expression of mammalian enzymes specific to methylated damaged sites in DNA may differentially influence the sensitivity of cells to alkylating agents [89,90]. Aberrant activity has been shown for many enzymes in various tumor types. Although AAG functions to remove damaged DNA bases, studies have shown that elevated enzyme levels can promote mutagenesis and genetic instability through excessive formation of apurinic/apyrimidinic sites [91,92,93].
It was shown that the mRNA and protein expression levels of AAG were higher in breast cancer samples compared to normal breast epithelium cells [94]. Nuclear staining showed that, in tumor cells, AAG can be located outside the nucleus. Such redistribution of AAG localization can be associated with the features of post-translational modifications in tumor cells, and lead to a decrease in DNA repair mechanisms in the nucleus despite higher expression levels of AAG protein [94].
The influence of AAG and OGG1 activity on the development of lung cancer in smoking and non-smoking patients was investigated [95]. It was shown that high AAG enzyme activity is associated with lung cancer risk, which is opposite to the effect of OGG1. At the same time, no relationship was found between smoking and high AAG activity.
The level of AAG expression was shown to be higher in glioma cells than in healthy brain tissue [96]. Using an immunohistochemistry assay, it was shown that the positive staining for AAG was mainly observed in the nuclei of tumor cells in glioma tissues, whereas its immunoreactivities in non-neoplastic brain sections ranged from undetectable to low. Liu et al. showed that the survival rate of patients with positive AAG staining was lower than those without. Further analysis showed a significantly worse overall survival for patients whose tumors had high AAG levels. This study has demonstrated the prognostic value of AAG levels in human cancers and the potential of high AAG protein levels as a marker of poor prognosis for patients with gliomas.
AAG confers resistance to temozolomide, a primary option for glioma treatment [97,98]. Furthermore, ulcerative colitis—a chronic inflammatory condition linked to colorectal cancer risk—demonstrates increased AAG activity [99]. In mouse models, AAG serves as a key suppressor of inflammation-induced colon cancer, where repair of methylation-induced DNA damage is critical for tumor suppression [100]. Mpg knockout mice infected with H. pylori exhibited greater susceptibility to preneoplastic gastric lesions [100].
AAG activity varies across the population, and alterations may contribute to cancer development/progression [95,101]. These variations may stem from AAG polymorphisms. While polymorphic variants have been identified in tumors, their functional impacts remain systematically uncharacterized.
Analysis of COSMIC (https://cancer.sanger.ac.uk/cosmic, accessed on 10 February 2025), cBioPortal (https://www.cbioportal.org, accessed on 10 February 2025) and National Cancer Institute (https://portal.gdc.cancer.gov, accessed on 10 February 2025) somatic mutation databases revealed numerous AAG missense mutations in tumors (Table S2). The AAG mutant variants were sorted by cancer type (Table 1). Polymorphic variants of the AAG enzyme were found in tumor tissues of different origins, which may indicate a general role of AAG in the development of cancer. Notably, variants R118Q, P130S, M164I, D175N, L180F and V264A were detected in brain cancers, where AAG’s therapeutic relevance was established [96,97,98].
We analyzed 93 SNP variants of AAG found in cancer samples present in databases (Table S2) and compared the obtained variants with the data in Table S1. Among them, 18 amino acid substitutions correspond to a high degree of negative impact, 7 substitutions correspond to a medium one, and 20 substitutions correspond to a low probability of negative impact on AAG function. Particularly noteworthy are variants that both predict functional impairment and occur in tumors (Table 2). These likely exhibit altered enzymatic properties affecting DNA interaction kinetics.
All amino acid substitutions are distributed throughout the protein globule (Figure 3). Also, we identified several conservative amino acid residues in this list: Glu125, Tyr127, Arg145, Pro153, Val158, Gly163 and Arg182. The catalytic residues Tyr127, Arg182, and Glu125 clearly explain their high-risk predictions. For other variants, functional consequences require further experimental confirmation.

6. Discussion

The alkyladenine DNA glycosylase AAG is responsible for the removal of a wide range of structurally different alkylated DNA bases. While AAG maintains genetic stability, elevated enzyme activity in certain tumor types confers resistance to chemotherapeutic drugs. The future investigation of AAG and its natural mutant variants can proceed in several directions, with potential implications for cancer biology, therapeutic development, and personalized medicine. The mechanistic insights into AAG dysregulation should be investigated. High-resolution structural studies (cryo-EM or X-ray crystallography) of AAG SNP variants could elucidate how specific SNPs alter enzyme–substrate interactions, catalytic efficiency or DNA-binding affinity. Systematic investigation of post-translational modifications (phosphorylation, acetylation) in AAG’s unstructured N-terminus may reveal regulatory mechanisms influencing its activity or localization in cancer cells. The functional characterization of predicted high-risk SNP variants should include in vitro assays and cellular model assays. Particular attention may be paid to establishing the role of SNPs leading to the substitution of non-conservative amino acid residues. The functional significance of most of these amino acid substitutions remains unclear and requires additional studies to confirm the predicted high negative impact on AAG function. Also, the examination of how AAG variants affect coordination with other DNA repair enzymes (for example, APE1, OGG1, Polβ, or the XRCC1/LigIII complex) can additionally provide insights into the dysregulation of DNA repair mechanisms.
Research into AAG polymorphic variants and their connection with various oncological and neurodegenerative diseases, including gene therapy and inhibitors, could enhance drug development. The repair of DNA damage is essential for preserving the integrity of genetic information and preventing the onset of numerous diseases. Gaining insight into how wild-type AAG and its polymorphic variants may relate to specific diseases may be useful for developing new treatments focused on modulating AAG activity. In this context, strategies aimed at both elevating AAG expression levels and creating inhibitors of its enzymatic activity may prove therapeutically beneficial. Elevating AAG expression levels may be advantageous in situations of excessive DNA damage, whereas developing inhibitors of AAG activity may aid in treating tumors with unregulated repair mechanisms. Investigating the impact of AAG polymorphisms on enzyme activity may assist in customizing treatment strategies to the distinct genetic profile of each patient, thereby enhancing the effectiveness of therapeutic interventions. Taken together, the dual role of AAG as a guardian of genomic stability and a potential driver of cancer underscores the need for a multidisciplinary approach.

7. Conclusions

The expression of enzyme polymorphic variants with modified activity may elevate the risk of cancer. Up to this point, only a limited number of studies have explored the role of AAG polymorphism in cancer progression. In this paper, we conducted a literature review as well as a bioinformatics analysis aimed at determining the impact of AAG polymorphic variants on its enzymatic characteristics. Over 370 missense SNPs were ranked based on their potential influence, with approximately 40% predicted to present a high-risk factor. The results obtained suggest a potential involvement of AAG polymorphic variants in the onset of oncological diseases. We compared the findings with data regarding the prevalence of specific SNPs in cancer samples. From the analysis, we identified 18 SNPs that combined the predicted negative impact and were detected in cancer samples. The majority of the identified mutations have not been functionally characterized previously and require experimental validation of the enzyme’s activity.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/ijms26157647/s1.

Author Contributions

Conceptualization, O.A.K.; methodology, O.A.K.; software, O.A.K.; validation, O.A.K. and A.A.K.; formal analysis, O.A.K.; investigation, O.A.K.; resources, O.A.K. and A.A.K.; data curation, O.A.K. and A.A.K.; writing—original draft preparation, O.A.K.; writing—review and editing, A.A.K.; visualization, O.A.K.; supervision, A.A.K.; project administration, A.A.K.; funding acquisition, O.A.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Russian Science Foundation, grant No. 25-24-00148.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are available upon request to O.A.K. Tel. +7 (383) 363-5174, E-mail: kladova@1bio.ru.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Friedberg, E.C.; Aguilera, A.; Gellert, M.; Hanawalt, P.C.; Hays, J.B.; Lehmann, A.R.; Lindahl, T.; Lowndes, N.; Sarasin, A.; Wood, R.D. DNA Repair: From Molecular Mechanism to Human Disease. DNA Repair. 2006, 5, 986–996. [Google Scholar] [CrossRef]
  2. Friedberg, E.C. Inroads into Base Excision Repair II: The Discovery of DNA Glycosylases. DNA Repair. 2004, 3, 1531–1536. [Google Scholar] [CrossRef] [PubMed]
  3. Friedberg, E.C. How Nucleotide Excision Repair Protects against Cancer. Nat. Rev. Cancer 2001, 1, 22–33. [Google Scholar] [CrossRef] [PubMed]
  4. Chatterjee, N.; Walker, G.C. Mechanisms of DNA Damage, Repair and Mutagenesis. Environ. Mol. Mutagen. 2017, 58, 235. [Google Scholar] [CrossRef] [PubMed]
  5. Gohil, D.; Sarker, A.H.; Roy, R. Base Excision Repair: Mechanisms and Impact in Biology, Disease, and Medicine. Int. J. Mol. Sci. 2023, 24, 14186. [Google Scholar] [CrossRef]
  6. Pascucci, B.; Stucki, M.; Jónsson, Z.O.; Dogliotti, E.; Hübscher, U. Long Patch Base Excision Repair with Purified Human Proteins: DNA Ligase I as Patch Size Mediator for DNA Polymerases δ and ε. J. Biol. Chem. 1999, 274, 33696–33702. [Google Scholar] [CrossRef]
  7. Krokan, H.E.; Bjørås, M. Base Excision Repair. Cold Spring Harb. Perspect. Biol. 2013, 5, a012583. [Google Scholar] [CrossRef]
  8. Fromme, J.C.; Verdine, G.L. Base Excision Repair. Adv. Protein Chem. 2004, 69, 1–41. [Google Scholar] [CrossRef]
  9. Seeberg, E.; Eide, L.; Bjørås, M. The Base Excision Repair Pathway. Trends Biochem. Sci. 1995, 20, 391–397. [Google Scholar] [CrossRef]
  10. Jagannathan, I.; Cole, H.A.; Hayes, J.J. Base Excision Repair in Nucleosome Substrates. Chromosome Res. 2006, 14, 27–37. [Google Scholar] [CrossRef]
  11. Jacobs, A.L.; Schär, P. DNA Glycosylases: In DNA Repair and Beyond. Chromosoma 2012, 121, 1–20. [Google Scholar] [CrossRef] [PubMed]
  12. Visnes, T.; Doseth, B.; Pettersen, H.S.; Hagen, L.; Sousa, M.M.L.; Akbari, M.; Otterlei, M.; Kavli, B.; Slupphaug, G.; Krokan, H.E. Uracil in DNA and Its Processing by Different DNA Glycosylases. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2009, 364, 563–568. [Google Scholar] [CrossRef] [PubMed]
  13. Faucher, F.; Doublié, S.; Jia, Z. 8-Oxoguanine DNA Glycosylases: One Lesion, Three Subfamilies. Int. J. Mol. Sci. 2012, 13, 6711–6729. [Google Scholar] [CrossRef] [PubMed]
  14. Gallinari, P.; Jiricny, J. A New Class of Uracil-DNA Glycosylases Related to Human Thymine-DNA Glycosylase. Nature 1996, 383, 735–738. [Google Scholar] [CrossRef]
  15. Rosenquist, T.A.; Zaika, E.; Fernandes, A.S.; Zharkov, D.O.; Miller, H.; Grollman, A.P. The Novel DNA Glycosylase, NEIL1, Protects Mammalian Cells from Radiation-Mediated Cell Death. DNA Repair. 2003, 2, 581–591. [Google Scholar] [CrossRef]
  16. Liu, P.; Burdzy, A.; Sowers, L.C. Substrate Recognition by a Family of Uracil-DNA Glycosylases: UNG, MUG, and TDG. Chem. Res. Toxicol. 2002, 15, 1001–1009. [Google Scholar] [CrossRef]
  17. Prakash, A.; Doublié, S.; Wallace, S.S. The Fpg/Nei Family of DNA Glycosylases. Prog. Mol. Biol. Transl. Sci. 2012, 110, 71–91. [Google Scholar]
  18. Demple, B.; Linn, S. DNA N-Glycosylases and UV Repair. Nature 1980, 287, 203–208. [Google Scholar] [CrossRef]
  19. Krokan, H.E.; Standal, R.; Slupphaug, G. DNA Glycosylases in the Base Excision Repair of DNA. Biochem. J. 1997, 325, 1–16. [Google Scholar] [CrossRef]
  20. Wallace, S.S. DNA Glycosylases Search for and Remove Oxidized DNA Bases. Environ. Mol. Mutagen. 2013, 54, 691–704. [Google Scholar] [CrossRef]
  21. Demple, B.; Sung, J.S. Molecular and Biological Roles of Ape1 Protein in Mammalian Base Excision Repair. DNA Repair. 2005, 4, 1442–1449. [Google Scholar] [CrossRef] [PubMed]
  22. Sobol, R.W.; Wilson, S.H. Mammalian DNA β-Polymerase in Base Excision Repair of Alkylation Damage. Prog. Nucleic Acid. Res. Mol. Biol. 2001, 68, 57–74. [Google Scholar]
  23. Kumar, A.; Widen, S.G.; Williams, K.R.; Kedar, P.; Karpel, R.L.; Wilson, S.H. Studies of the Domain Structure of Mammalian DNA Polymerase Beta. Identification of a Discrete Template Binding Domain. J. Biol. Chem. 1990, 265, 2124–2131. [Google Scholar] [CrossRef]
  24. Beard, W.A.; Wilson, S.H. DNA Polymerase Beta and Other Gap-Filling Enzymes in Mammalian Base Excision Repair. In Enzymes; Academic Press: Cambridge, MA, USA, 2019; Volume 45, pp. 1–26. ISBN 9780128173961. [Google Scholar]
  25. Campalans, A.; Marsin, S.; Nakabeppu, Y.; O’Connor, T.R.; Boiteux, S.; Radicella, J.P. XRCC1 Interactions with Multiple DNA Glycosylases: A Model for Its Recruitment to Base Excision Repair. DNA Repair. 2005, 4, 826–835. [Google Scholar] [CrossRef]
  26. Cannan, W.J.; Rashid, I.; Tomkinson, A.E.; Wallace, S.S.; Pederson, D.S. The Human Ligase IIIα-XRCC1 Protein Complex Performs DNA Nick Repair after Transient Unwrapping of Nucleosomal DNA. J. Biol. Chem. 2017, 292, 5227–5238. [Google Scholar] [CrossRef]
  27. Dianova, I.I.; Sleeth, K.M.; Allinson, S.L.; Parsons, J.L.; Breslin, C.; Caldecott, K.W.; Dianov, G.L. XRCC1-DNA Polymerase β Interaction Is Required for Efficient Base Excision Repair. Nucleic Acids Res. 2004, 32, 2550–2555. [Google Scholar] [CrossRef]
  28. Marintchev, A.; Robertson, A.; Dimitriadis, E.K.; Prasad, R.; Wilson, S.H.; Mullen, G.P. Domain Specific Interaction in the XRCC1-DNA Polymerase Beta Complex. Nucleic Acids Res. 2000, 28, 2049–2059. [Google Scholar] [CrossRef]
  29. Nash, R.A.; Caldecott, K.W.; Barnes, D.E.; Lindahl, T. XRCC1 Protein Interacts with One of Two Distinct Forms of DNA Ligase III. Biochemistry 1997, 36, 5207–5211. [Google Scholar] [CrossRef]
  30. Odell, I.D.; Barbour, J.-E.; Murphy, D.L.; Della-Maria, J.A.; Sweasy, J.B.; Tomkinson, A.E.; Wallace, S.S.; Pederson, D.S. Nucleosome Disruption by DNA Ligase III-XRCC1 Promotes Efficient Base Excision Repair. Mol. Cell Biol. 2011, 31, 4623–4632. [Google Scholar] [CrossRef]
  31. Li, Y. DNA Adducts in Cancer Chemotherapy. J. Med. Chem. 2024, 67, 5113–5143. [Google Scholar] [CrossRef]
  32. Kondo, N.; Takahashi, A.; Ono, K.; Ohnishi, T. DNA Damage Induced by Alkylating Agents and Repair Pathways. J. Nucleic Acids 2010, 2010, 543531. [Google Scholar] [CrossRef] [PubMed]
  33. Plosky, B.; Samson, L.; Engelward, B.P.; Gold, B.; Schlaen, B.; Millas, T.; Magnotti, M.; Schor, J.; Scicchitano, D.A. Base Excision Repair and Nucleotide Excision Repair Contribute to the Removal of N-Methylpurines from Active Genes. DNA Repair. 2002, 1, 683–696. [Google Scholar] [CrossRef] [PubMed]
  34. Sedgwick, B.; Bates, P.A.; Paik, J.; Jacobs, S.C.; Lindahl, T. Repair of Alkylated DNA: Recent Advances. DNA Repair. 2007, 6, 429–442. [Google Scholar] [CrossRef] [PubMed]
  35. Gentil, A.; Cabral-Neto, J.B.; Mariage-Samson, R.; Margot, A.; Imbach, J.L.; Rayner, B.; Sarasin, A. Mutagenicity of a Unique Apurinic/Apyrimidinic Site in Mammalian Cells. J. Mol. Biol. 1992, 227, 981–984. [Google Scholar] [CrossRef]
  36. Wilson, D.M.; Barsky, D. The Major Human Abasic Endonuclease: Formation, Consequences and Repair of Abasic Lesions in DNA. Mutat. Res.-DNA Repair. 2001, 485, 283–307. [Google Scholar] [CrossRef]
  37. Carles, J.; Monzo, M.; Amat, M.; Jansa, S.; Artells, R.; Navarro, A.; Foro, P.; Alameda, F.; Gayete, A.; Gel, B.; et al. Single-Nucleotide Polymorphisms in Base Excision Repair, Nucleotide Excision Repair, and Double Strand Break Genes as Markers for Response to Radiotherapy in Patients with Stage I to II Head-and-Neck Cancer. Int. J. Radiat. Oncol. Biol. Phys. 2006, 66, 1022–1030. [Google Scholar] [CrossRef]
  38. Kiyohara, C.; Takayama, K.; Nakanishi, Y. Association of Genetic Polymorphisms in the Base Excision Repair Pathway with Lung Cancer Risk: A Meta-Analysis. Lung Cancer 2006, 54, 267–283. [Google Scholar] [CrossRef]
  39. Figueroa, J.D.; Malats, N.; Real, F.X.; Silverman, D.; Kogevinas, M.; Chanock, S.; Welch, R.; Dosemeci, M.; Tardón, A.; Serra, C.; et al. Genetic Variation in the Base Excision Repair Pathway and Bladder Cancer Risk. Hum. Genet. 2007, 121, 233–242. [Google Scholar] [CrossRef]
  40. Jacob, K.D.; Hooten, N.N.; Tadokoro, T.; Lohani, A.; Barnes, J.; Evans, M.K. Alzheimer’s Disease-Associated Polymorphisms in Human OGG1 Alter Catalytic Activity and Sensitize Cells to DNA Damage. Free Radic. Biol. Med. 2013, 63, 115–125. [Google Scholar] [CrossRef]
  41. Hollis, T.; Ichikawa, Y.; Ellenberger, T. DNA Bending and a Flip-out Mechanism for Base Excision by the Helix-Hairpin-Helix DNA Glycosylase, Escherichia Coli AlkA. EMBO J. 2000, 19, 758–766. [Google Scholar] [CrossRef]
  42. Labahn, J.; Schärer, O.D.; Long, A.; Ezaz-Nikpay, K.; Verdine, G.L.; Ellenberger, T.E. Structural Basis for the Excision Repair of Alkylation-Damaged DNA. Cell 1996, 86, 321–329. [Google Scholar] [CrossRef]
  43. Rubinson, E.H.; Gowda, A.S.P.; Spratt, T.E.; Gold, B.; Eichman, B.F. An Unprecedented Nucleic Acid Capture Mechanism for Excision of DNA Damage. Nature 2010, 468, 406–413. [Google Scholar] [CrossRef][Green Version]
  44. Lau, A.Y.; Schä, O.D.; Samson, L.; Verdine, G.L.; Ellenberger, T. Crystal Structure of a Human Alkylbase-DNA Repair Enzyme Complexed to DNA: Mechanisms for Nucleotide Flipping and Base Excision. Cell 1998, 95, 249–258. [Google Scholar] [CrossRef]
  45. Thayer, M.M.; Ahern, H.; Xing, D.; Cunningham, R.P.; Tainer, J. A Novel DNA Binding Motifs in the DNA Repair Enzyme Endonuclease III Crystal Structure. EMBO J. 1995, 14, 4108–4120. [Google Scholar] [CrossRef] [PubMed]
  46. Doherty, A.J.; Serpell, L.C.; Ponting, C.P. The Helix-Hairpin-Helix DNA-Binding Motif: A Structural Basis for Non-Sequence-Specific Recognition of DNA. Nucleic Acids Res. 1996, 24, 2488–2497. [Google Scholar] [CrossRef] [PubMed]
  47. Yamagata, Y.; Kato, M.; Odawara, K.; Tokuno, Y.; Nakashima, Y.; Matsushima, N.; Yasumura, K.; Tomita, K.; Ihara, K.; Fujii, Y.; et al. Three-Dimensional Structure of a DNA Repair Enzyme, 3-Methyladenine DNA Glycosylase II, from Escherichia Coli. Cell 1996, 86, 311–319. [Google Scholar] [CrossRef] [PubMed]
  48. Rubinson, E.H.; Eichman, B.F. Nucleic Acid Recognition by Tandem Helical Repeats. Curr. Opin. Struct. Biol. 2012, 22, 101–109. [Google Scholar] [CrossRef][Green Version]
  49. Izumi, T.; Tatsuka, M.; Tano, K.; Asano, M.; Mitra, S. Molecular Cloning and Characterization of the Promoter of the Human N-Methylpurine-DNA Glycosylase (MPG) Gene. Carcinogenesis 1997, 18, 1837–1839. [Google Scholar] [CrossRef][Green Version]
  50. Samson, L.; Derfler, B.; Boosalis, M.; Call, K. Cloning and Characterization of a 3-Methyladenine DNA Glycosylase CDNA from Human Cells Whose Gene Maps to Chromosome 16. Proc. Natl. Acad. Sci. USA 1991, 88, 9127–9131. [Google Scholar] [CrossRef]
  51. Vickers, M.A.; Vyas, P.; Harris, P.C.; Simmons, D.L.; Higgs, D.R. Structure of the Human 3-Methyladenine DNA Glycosylase Gene and Localization Close to the 16p Telomere. Proc. Natl. Acad. Sci. USA 1993, 90, 3437–3441. [Google Scholar] [CrossRef]
  52. Montaldo, N.P.; Bordin, D.L.; Brambilla, A.; Rösinger, M.; Fordyce Martin, S.L.; Bjørås, K.Ø.; Bradamante, S.; Aas, P.A.; Furrer, A.; Olsen, L.C.; et al. Alkyladenine DNA Glycosylase Associates with Transcription Elongation to Coordinate DNA Repair with Gene Expression. Nat. Commun. 2019, 10, 5460. [Google Scholar] [CrossRef]
  53. Beranek, D.T. Distribution of Methyl and Ethyl Adducts Following Alkylation with Monofunctional Alkylating Agents. Mutat. Res./Fundam. Mol. Mech. Mutagen. 1990, 231, 11–30. [Google Scholar] [CrossRef]
  54. Mao, P.; Brown, A.J.; Malc, E.P.; Mieczkowski, P.A.; Smerdon, M.J.; Roberts, S.A.; Wyrick, J.J. Genome-Wide Maps of Alkylation Damage, Repair, and Mutagenesis in Yeast Reveal Mechanisms of Mutational Heterogeneity. Genome Res. 2017, 27, 1674–1684. [Google Scholar] [CrossRef] [PubMed]
  55. Sheng, Y.; Sun, B.; Guo, W.T.; Zhang, Y.H.; Liu, X.; Xing, Y.; Dong, D.L. 3-Methyladenine Induces Cell Death and Its Interaction with Chemotherapeutic Drugs Is Independent of Autophagy. Biochem. Biophys. Res. Commun. 2013, 432, 5–9. [Google Scholar] [CrossRef] [PubMed]
  56. Lee, C.Y.I.; Delaney, J.C.; Kartalou, M.; Lingaraju, G.M.; Maor-Shoshani, A.; Essigmann, J.M.; Samson, L.D. Recognition and Processing of a New Repertoire of DNA Substrates by Human 3-Methyladenine DNA Glycosylase (AAG). Biochemistry 2009, 48, 1850–1861. [Google Scholar] [CrossRef] [PubMed]
  57. Maher, R.L.; Vallur, A.C.; Feller, J.A.; Bloom, L.B. Slow Base Excision by Human Alkyladenine DNA Glycosylase Limits the Rate of Formation of AP Sites and AP Endonuclease 1 Does Not Stimulate Base Excision. DNA Repair. 2007, 6, 71–81. [Google Scholar] [CrossRef]
  58. Wang, P.; Guliaev, A.B.; Elder, R.H.; Hang, B. Alkylpurine-DNA-N-Glycosylase Excision of 7-(Hydroxymethyl)-1,N 6-Ethenoadenine, a Glycidaldehyde-Derived DNA Adduct. DNA Repair. 2006, 5, 23–31. [Google Scholar] [CrossRef]
  59. Hang, B.; Singer, B.; Margison, G.P.; Elder, R.H. Targeted Deletion of Alkylpurine-DNA-N-Glycosylase in Mice Eliminates Repair of 1,N6-Ethenoadenine and Hypoxanthine but Not of 3,N4-Ethenocytosine or 8-Oxoguanine. Proc. Natl. Acad. Sci. USA 1997, 94, 12869–12874. [Google Scholar] [CrossRef]
  60. Hitchcock, T.M.; Dong, L.; Connor, E.E.; Meira, L.B.; Samson, L.D.; Wyatt, M.D.; Cao, W. Oxanine DNA Glycosylase Activity from Mammalian Alkyladenine Glycosylase. J. Biol. Chem. 2004, 279, 38177–38183. [Google Scholar] [CrossRef]
  61. Fu, D.; Samson, L.D. Direct Repair of 3,N(4)-Ethenocytosine by the Human ALKBH2 Dioxygenase Is Blocked by the AAG/MPG Glycosylase. DNA Repair 2012, 11, 46–52. [Google Scholar] [CrossRef]
  62. Gros, L.; Maksimenko, A.V.; Privezentzev, C.V.; Laval, J.; Saparbaev, M.K. Hijacking of the Human Alkyl-N-Purine-DNA Glycosylase by 3,N4-Ethenocytosine, a Lipid Peroxidation-Induced DNA Adduct. J. Biol. Chem. 2004, 279, 17723–17730. [Google Scholar] [CrossRef]
  63. Nemec, A.A.; Wallace, S.S.; Sweasy, J.B. Variant Base Excision Repair Proteins: Contributors to Genomic Instability. Semin. Cancer Biol. 2010, 20, 320. [Google Scholar] [CrossRef]
  64. Datkhile, K.D.; Durgawale, P.P.; Patil, M.N.; Gudur, R.A.; Gudur, A.K.; Patil, S.R. Impact of Polymorphism in Base Excision Repair and Nucleotide Excision Repair Genes and Risk of Cervical Cancer: A Case-Control Study. Asian Pac. J. Cancer Prev. 2022, 23, 1291. [Google Scholar] [CrossRef] [PubMed]
  65. Wang, X.; Yue, H.; Li, S.; Guo, J.; Guan, Z.; Zhu, Z.; Niu, B.; Zhang, T.; Wang, J. Genetic Polymorphisms in DNA Repair Gene APE1/Ref-1 and the Risk of Neural Tube Defects in a High-Risk Area of China. Reprod. Sci. 2021, 28, 2592–2601. [Google Scholar] [CrossRef] [PubMed]
  66. Starcevic, D.; Dalal, S.; Sweasy, J.B. Is There a Link Between DNA Polymerase Beta and Cancer? Cell Cycle 2004, 3, 998–1001. [Google Scholar] [CrossRef] [PubMed]
  67. Zhao, G.Q.; Wang, T.; Zhao, Q.; Yang, H.Y.; Tan, X.H.; Dong, Z.M. Mutation of DNA Polymerase β in Esophageal Carcinoma of Different Regions. World J. Gastroenterol. WJG 2005, 11, 4618. [Google Scholar] [CrossRef]
  68. Murphy, D.L.; Donigan, K.A.; Jaeger, J.; Sweasy, J.B. The E288K Colon Tumor Variant of DNA Polymerase β Is a Sequence Specific Mutator. Biochemistry 2012, 51, 5269–5275. [Google Scholar] [CrossRef]
  69. Galick, H.A.; Marsden, C.G.; Kathe, S.; Dragon, J.A.; Volk, L.; Nemec, A.A.; Wallace, S.S.; Prakash, A.; Doublié, S.; Sweasy, J.B. The NEIL1 G83D Germline DNA Glycosylase Variant Induces Genomic Instability and Cellular Transformation. Oncotarget 2017, 8, 85883. [Google Scholar] [CrossRef]
  70. Almutairi, F.; Ali Khan Pathan, A.; Alanazi, M.; Shalaby, M.; Alabdulkarim, H.A.; Alamri, A.; Al Naeem, A.; Elrobh, M.; Shaik, J.P.; Khan, W.; et al. Association of DNA Repair Gene APE1 Asp148Glu Polymorphism with Breast Cancer Risk. Dis. Markers 2015, 2015, 869512. [Google Scholar] [CrossRef]
  71. Dai, Z.J.; Shao, Y.P.; Kang, H.F.; Tang, W.; Xu, D.; Zhao, Y.; Liu, D.; Wang, M.; Yang, P.T.; Wang, X.J. Relationship between Apurinic Endonuclease 1 Asp148Glu Polymorphism and Gastrointestinal Cancer Risk: An Updated Meta-Analysis. World J. Gastroenterol. 2015, 21, 5081–5089. [Google Scholar] [CrossRef]
  72. Cai, L.; Fu, Y.; Zhang, Y. APE1 Asp148Glu Polymorphism and Lung Cancer Susceptibility. Tumor Biol. 2014, 35, 5237–5244. [Google Scholar] [CrossRef] [PubMed]
  73. Illuzzi, J.L.; Harris, N.A.; Manvilla, B.A.; Kim, D.; Li, M.; Drohat, A.C.; Wilson, D.M. Functional Assessment of Population and Tumor-Associated APE1 Protein Variants. PLoS ONE 2013, 8, e65922. [Google Scholar] [CrossRef] [PubMed]
  74. Adhikari, S.; Chetram, M.A.; Woodrick, J.; Mitra, P.S.; Manthena, P.V.; Khatkar, P.; Dakshanamurthy, S.; Dixon, M.; Karmahapatra, S.K.; Nuthalapati, N.K.; et al. Germ Line Variants of Human N-Methylpurine DNA Glycosylase Show Impaired DNA Repair Activity and Facilitate 1,N6-Ethenoadenine-Induced Mutations. J. Biol. Chem. 2015, 290, 4966. [Google Scholar] [CrossRef]
  75. Huang, C.M.; Chen, S.Y.; Huang, P.H.; Tsai, F.J. Effect of MPG Gene Rs2858056 Polymorphism, Copy Number Variation, and Level of Serum MPG Protein on the Risk for Rheumatoid Arthritis. PLoS ONE 2015, 10, e0120699. [Google Scholar] [CrossRef]
  76. Chen, S.Y.; Wan, L.; Huang, C.M.; Huang, Y.C.; Sheu, J.J.C.; Lin, Y.J.; Liu, S.P.; Lan, Y.C.; Lai, C.H.; Lin, C.W.; et al. Genetic Polymorphisms of the DNA Repair Gene MPG May Be Associated with Susceptibility to Rheumatoid Arthritis. J. Appl. Genet. 2010, 51, 519–521. [Google Scholar] [CrossRef]
  77. Ng, P.C.; Henikoff, S. Predicting Deleterious Amino Acid Substitutions. Genome Res. 2001, 11, 863. [Google Scholar] [CrossRef]
  78. Ng, P.C.; Henikoff, S. SIFT: Predicting Amino Acid Changes That Affect Protein Function. Nucleic Acids Res. 2003, 31, 3812–3814. [Google Scholar] [CrossRef]
  79. Ramensky, V.; Bork, P.; Sunyaev, S. Human Non-Synonymous SNPs: Server and Survey. Nucleic Acids Res. 2002, 30, 3894–3900. [Google Scholar] [CrossRef]
  80. Adzhubei, I.; Jordan, D.M.; Sunyaev, S.R. Predicting Functional Effect of Human Missense Mutations Using PolyPhen-2. In Current Protocols in Human Genetics; Wiley: Hoboken, NJ, USA, 2013. [Google Scholar] [CrossRef]
  81. Martin, K.; Daniela, M.W.; Preti, J.; Brain, J.O.; Gregory, M.C.; Jay, S. A General Framework for Estimating the Relative Pathogenicity of Human Genetic Variants. Nat. Genet. 2014, 46, 310–315. [Google Scholar] [CrossRef]
  82. Schubach, M.; Maass, T.; Nazaretyan, L.; Röner, S.; Kircher, M. CADD v1.7: Using Protein Language Models, Regulatory CNNs and Other Nucleotide-Level Scores to Improve Genome-Wide Variant Predictions. Nucleic Acids Res. 2024, 52, D1143–D1154. [Google Scholar] [CrossRef]
  83. Schwarz, J.M.; Cooper, D.N.; Schuelke, M.; Seelow, D. MutationTaster2: Mutation Prediction for the Deep-Sequencing Age. Nat. Methods 2014, 11, 361–362. [Google Scholar] [CrossRef] [PubMed]
  84. Schwarz, J.M.; Rödelsperger, C.; Schuelke, M.; Seelow, D. MutationTaster Evaluates Disease-Causing Potential of Sequence Alterations. Nat. Methods 2010, 7, 575–576. [Google Scholar] [CrossRef] [PubMed]
  85. Li, C.; Zhi, D.; Wang, K.; Liu, X. MetaRNN: Differentiating Rare Pathogenic and Rare Benign Missense SNVs and InDels Using Deep Learning. Genome Med. 2022, 14, 115. [Google Scholar] [CrossRef] [PubMed]
  86. Choi, Y.; Sims, G.E.; Murphy, S.; Miller, J.R.; Chan, A.P. Predicting the Functional Effect of Amino Acid Substitutions and Indels. PLoS ONE 2012, 7, e46688. [Google Scholar] [CrossRef]
  87. Choi, Y.; Chan, A.P. PROVEAN Web Server: A Tool to Predict the Functional Effect of Amino Acid Substitutions and Indels. Bioinformatics 2015, 31, 2745–2747. [Google Scholar] [CrossRef]
  88. Wallace, S.S.; Murphy, D.L.; Sweasy, J.B. Base Excision Repair and Cancer. Cancer Lett. 2012, 327, 73–89. [Google Scholar] [CrossRef]
  89. Ibeanu, G.; Hartenstein, B.; Dunn, W.C.; Chang, L.Y.; Hofmann, E.; Coquerelle, T.; Mitra, S.; Kaina, B. Overexpression of Human DNA Repair Protein N-Methylpurine-DNA Glycosylase Results in the Increased Removal of N-Methylpurines in DNA without a Concomitant Increase in Resistance to Alkylating Agents in Chinese Hamster Ovary Cells. Carcinogenesis 1992, 13, 1989–1995. [Google Scholar] [CrossRef]
  90. Habraken, Y.; Laval, F. Increased Resistance of the Chinese Hamster Mutant Irsl Cells to Monofunctional Alkylating Agents by Transfection of the E. Coli or Mammalian N3-Methyladenine-DNA-Glycosylase Genes. Mutat. Res.-DNA Repair. 1993, 293, 187–195. [Google Scholar] [CrossRef]
  91. Klapacz, J.; Lingaraju, G.M.; Guo, H.H.; Shah, D.; Moar-Shoshani, A.; Loeb, L.A.; Samson, L.D. Frameshift Mutagenesis and Microsatellite Instability Induced by Human Alkyladenine DNA Glycosylase. Mol. Cell 2010, 37, 843. [Google Scholar] [CrossRef][Green Version]
  92. Sobol, R.W.; Prasad, R.; Evenski, A.; Baker, A.; Yang, X.P.; Horton, J.K.; Wilson, S.H. The Lyase Activity of the DNA Repair Protein β-Polymerase Protects from DNA-Damage-Induced Cytotoxicity. Nature 2000, 405, 807–810. [Google Scholar] [CrossRef]
  93. Kothandapani, A.; Dangeti, V.S.M.N.; Brown, A.R.; Banze, L.A.; Wang, X.H.; Sobol, R.W.; Patrick, S.M. Novel Role of Base Excision Repair in Mediating Cisplatin Cytotoxicity. J. Biol. Chem. 2011, 286, 14564–14574. [Google Scholar] [CrossRef]
  94. Cerda, S.R.; Turk, P.W.; Thor, A.D.; Weitzman, S.A. Altered Expression of the DNA Repair Protein, N-Methylpurine-DNA Glycosylase (MPG), in Breast Cancer. FEBS Lett. 1998, 431, 12–18. [Google Scholar] [CrossRef]
  95. Leitner-Dagan, Y.; Sevilya, Z.; Pinchev, M.; Kramer, R.; Elinger, D.; Roisman, L.C.; Rennert, H.S.; Schechtman, E.; Freedman, L.; Rennert, G.; et al. N-Methylpurine DNA Glycosylase and OGG1 DNA Repair Activities: Opposite Associations with Lung Cancer Risk. J. Natl. Cancer Inst. 2012, 104, 1765–1769. [Google Scholar] [CrossRef]
  96. Liu, C.; Tu, Y.; Yuan, J.; Mao, X.; He, S.; Wang, L.; Fu, G.; Zong, J.; Zhang, Y. Aberrant Expression of N-Methylpurine-DNA Glycosylase Influences Patient Survival in Malignant Gliomas. J. Biomed. Biotechnol. 2012, 2012, 760679. [Google Scholar] [CrossRef]
  97. Tang, J.B.; Svilar, D.; Trivedi, R.N.; Wang, X.H.; Goellner, E.M.; Moore, B.; Hamilton, R.L.; Banze, L.A.; Brown, A.R.; Sobol, R.W. N-Methylpurine DNA Glycosylase and DNA Polymerase Beta Modulate BER Inhibitor Potentiation of Glioma Cells to Temozolomide. Neuro Oncol. 2011, 13, 471–486. [Google Scholar] [CrossRef] [PubMed]
  98. Serrano-Heras, G.; Castro-Robles, B.; Romero-Sánchez, C.M.; Carrión, B.; Barbella-Aponte, R.; Sandoval, H.; Segura, T. Involvement of N-Methylpurine DNA Glycosylase in Resistance to Temozolomide in Patient-Derived Glioma Cells. Sci. Rep. 2020, 10, 22185. [Google Scholar] [CrossRef] [PubMed]
  99. Hofseth, L.J.; Khan, M.A.; Ambrose, M.; Nikolayeva, O.; Xu-Welliver, M.; Kartalou, M.; Hussain, S.P.; Roth, R.B.; Zhou, X.; Mechanic, L.E.; et al. The Adaptive Imbalance in Base Excision–Repair Enzymes Generates Microsatellite Instability in Chronic Inflammation. J. Clin. Investig. 2003, 112, 1887. [Google Scholar] [CrossRef] [PubMed]
  100. Meira, L.B.; Bugni, J.M.; Green, S.L.; Lee, C.-W.; Pang, B.; Borenshtein, D.; Rickman, B.H.; Rogers, A.B.; Moroski-Erkul, C.A.; McFaline, J.L.; et al. DNA Damage Induced by Chronic Inflammation Contributes to Colon Carcinogenesis in Mice. J. Clin. Investig. 2008, 118, 2516–2525. [Google Scholar] [CrossRef]
  101. Speina, E.; Zielińska, M.; Barbin, A.; Gackowski, D.; Kowalewski, J.; Graziewicz, M.A.; Siedlecki, J.A.; Oliński, R.; Tudek, B. Decreased Repair Activities of 1,N6-Ethenoadenine and 3,N4-Ethenocytosine in Lung Adenocarcinoma Patients1. Cancer Res. 2003, 63, 4351–4357. Available online: https://aacrjournals.org/cancerres/article/63/15/4351/510303/Decreased-Repair-Activities-of-1-N6-Ethenoadenine (accessed on 7 February 2025).
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Figure 1. Structure of the AAG enzyme in complex with DNA containing 3,N4-ethenocytosine residue (PDB ID:3QI5). The enzyme is gray, DNA is blue, and the 3,N4-ethenocytosine residue is orange. The amino acid residues involved in catalysis and coordination of the damaged DNA base are highlighted in green. Glu125 and Arg182 participate in the coordination and deprotonation of the water molecule necessary for hydrolysis of the N-glycosidic bond. Tyr127 and Tyr159 contribute to the correct orientation of the damaged nucleotide in the enzyme active site.
Figure 1. Structure of the AAG enzyme in complex with DNA containing 3,N4-ethenocytosine residue (PDB ID:3QI5). The enzyme is gray, DNA is blue, and the 3,N4-ethenocytosine residue is orange. The amino acid residues involved in catalysis and coordination of the damaged DNA base are highlighted in green. Glu125 and Arg182 participate in the coordination and deprotonation of the water molecule necessary for hydrolysis of the N-glycosidic bond. Tyr127 and Tyr159 contribute to the correct orientation of the damaged nucleotide in the enzyme active site.
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Figure 2. Cleavable AAG substrates.
Figure 2. Cleavable AAG substrates.
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Figure 3. The location of amino acid residues in the AAG molecule with a predicted high negative impact. The protein globule is shown in gray, the highlighted amino acid residues are shown in red. PDB ID:3QI5.
Figure 3. The location of amino acid residues in the AAG molecule with a predicted high negative impact. The protein globule is shown in gray, the highlighted amino acid residues are shown in red. PDB ID:3QI5.
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Table 1. Amino acid mutations found in tumor samples according to COSMIC/cBioPortal/Portal.gdc.cancer.gov databases.
Table 1. Amino acid mutations found in tumor samples according to COSMIC/cBioPortal/Portal.gdc.cancer.gov databases.
Cancers by Body Location/SystemAAG Mutations
BreastS47T, R100W, R120C, M151I
Digestive/GastrointestinalA5T, Q20H, R24Q, P25A, A28T, D36N, A37T, S47T, R60C, P64L, R72S, I74M, E89D, R100Q, R100W, L103V, R120H, E123V, E125K, Y127C, R145H, R147Q, G148S, M151I, P153L, G163D, G163S, R182Q, G189D, R197C, R201W, A205D, D211N, R212H, L214F, A226T, D239G, R246C, R246P, P254S, V264I, G265S, G281C
EndocrineR194S, R197S, Q223P, P248A
GenitourinaryP112S, V158M, L180F, K202R, R261Q, H266N, F277L
GynecologicA5D, A5T, R17W, K21N, A38T, D50N, P65L, P68L, P94L, G114D, R118Q, M151I, P153Q, T192I, R207H, D211Y, E293K
Head and NeckG265S
Hematologic/BloodR17Q, T124I, S172R, H266Y
MusculoskeletalR24Q
NeurologicR118Q, P130S, M164I, D175N, L180F, V264A
Respiratory/
Thoracic		A52S, S77L, L180F, R246H, S282R
SkinM22Q, S48L, R120H, M168I, R201Q, E213K, P248S, R261W, E269K, R272Q, L275I, R280W
Table 2. The dbSNP-derived AAG SNPs also found in tumor samples according to COSMIC, cBioPortal and National Cancer Institute databases.
Table 2. The dbSNP-derived AAG SNPs also found in tumor samples according to COSMIC, cBioPortal and National Cancer Institute databases.
№SNPPredicted EffectCancer TypeConservation of Amino Acid Residue
1P94LHighEndometrioid carcinomaNon conserved
2R100WHighStomach carcinoma, breast carcinomaNon conserved
3R120CHighBreast carcinomaNon conserved
4E125KHighUpper aerodigestive tract carcinomaConserved
5Y127CHighLarge intestine adenocarcinomaConserved
6R145HHighStomach carcinomaConserved
7P153LHighStomach carcinomaConserved
8V158MHighKidney carcinoma, clear cell renal cell carcinomaConserved
9G163SHighLarge intestine adenocarcinomaConserved
10R182QHighLarge intestine adenocarcinomaConserved
11R197CHighEsophagus adenocarcinomaNon conserved
12R207HHighEndometrioid carcinoma, uterine adenomas and adenocarcinomasNon conserved
13R261QHighUrinary tract carcinomaNon conserved
14R261WHighMalignant melanomaNon conserved
15E269KHighMalignant melanomaNon conserved
16R280WHighCutaneous melanomaNon conserved
17G281CHighStomach adenocarcinomaNon conserved
18E293KHighCervix carcinoma, squamous cell carcinomaNon conserved
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Kladova, O.A.; Kuznetsova, A.A. The Link Between Human Alkyladenine DNA Glycosylase and Cancer Development. Int. J. Mol. Sci. 2025, 26, 7647. https://doi.org/10.3390/ijms26157647

AMA Style

Kladova OA, Kuznetsova AA. The Link Between Human Alkyladenine DNA Glycosylase and Cancer Development. International Journal of Molecular Sciences. 2025; 26(15):7647. https://doi.org/10.3390/ijms26157647

Chicago/Turabian Style

Kladova, Olga A., and Aleksandra A. Kuznetsova. 2025. "The Link Between Human Alkyladenine DNA Glycosylase and Cancer Development" International Journal of Molecular Sciences 26, no. 15: 7647. https://doi.org/10.3390/ijms26157647

APA Style

Kladova, O. A., & Kuznetsova, A. A. (2025). The Link Between Human Alkyladenine DNA Glycosylase and Cancer Development. International Journal of Molecular Sciences, 26(15), 7647. https://doi.org/10.3390/ijms26157647

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