The Link Between Human Alkyladenine DNA Glycosylase and Cancer Development

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.

Keywords: DNA repair; DNA repair coordination; alkyladenine DNA glycosylase; enzymatic activity; single-nucleotide polymorphism.

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 2

Cleavable AAG substrates.

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.