Kladova Olga A, Kuznetsova Aleksandra A
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia.
Int J Mol Sci. 2025 Aug 7;26(15):7647. doi: 10.3390/ijms26157647.
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.
烷基腺嘌呤 DNA 糖基化酶（AAG）是碱基切除修复（BER）途径中的一种关键酶，负责去除多种烷基化的 DNA 损伤。虽然 AAG 维持基因组稳定性，但活性失调与癌症发展、耐药性和神经退行性疾病有关。本综述综合了关于 AAG 的结构、催化机制和多态性变体的现有知识，强调了它们在疾病发病机制中的潜在作用。对 370 多个 AAG 单核苷酸多态性（SNP）进行了全面的生物信息学分析，确定约 40%为可能损害酶功能的高风险变体。值得注意的是，151 个 SNP 被多种算法预测具有破坏性，包括催化残基处的替换以及功能后果未知的非保守位点处的替换。对癌症数据库（COSMIC、cBioPortal、NCBI）的分析揭示了 93 个与肿瘤相关的 AAG 变体，其中 18 个被归类为高影响突变。这项工作强调了使用结构生物学、细胞模型和临床相关性分析对 AAG 变体进行机制研究的必要性。解读 AAG 的多态性格局可能会为癌症预防和治疗带来个性化策略。
