DNA Repair Mechanisms and Enzymatic Glycosylation

Cells continually encounter endogenous and exogenous lesions that threaten genomic integrity. Among the principal pathways that safeguard DNA are nucleotide excision repair, mismatch repair and base excision repair (BER). BER orchestrates a stepwise removal of damaged, inappropriate or modified bases through the activity of DNA glycosylases, enzymes that cleave the N-glycosidic bond to generate an abasic site. Subsequent processing by apurinic/apyrimidinic endonucleases, polymerases and ligases restores the canonical base pair. DNA glycosylases such as uracil-DNA glycosylase (UNG), single-stranded monofunctional uracil DNA-glycosylase (SMUG1), methyl-CpG binding domain protein 4 (MBD4) and thymine DNA glycosylase (TDG) each exhibit distinct substrate specificities, recognising uracil, oxidised bases and mismatches arising from deamination or epigenetic modifications. The efficiency and selectivity of these enzymes depend on the deformability of the DNA helix around the lesion, the base-flipping mechanism by which the target nucleotide is extruded from the duplex into the catalytic site, and the dynamics of enzyme–DNA turnover. Beyond repair, glycosylase-mediated excision of oxidised or methylated cytosine derivatives underpins active DNA demethylation and epigenetic programming. Recent advances have elucidated how DNA flexibility modulates glycosylase activity, how glycosylases coordinate with downstream factors to stimulate turnover and how aberrant base removal can contribute to mutagenesis, cytotoxicity and disease.

Research from Nature Portfolio

Investigations into uracil-DNA glycosylase (UNG) have revealed that the intrinsic deformability of DNA around a uracil lesion dictates excision efficiency. Time-resolved fluorescence spectroscopy, nuclear magnetic resonance and molecular dynamics simulations established a direct correlation between local flexibility modes and the specificity constant (k_cat/K_M) of UNG. Bases flanking the uracil are allosterically coupled, amplifying or attenuating DNA bending and base-flipping kinetics. This work demonstrates that substrate flexibility is a general determinant of glycosylase activity, with implications for understanding mutation hotspot formation, the evolution of repair specificity and the design of precision base-editing tools.

DNA Repair Mechanisms and Enzymatic Glycosylation publication trend

The graph below shows the total number of articles in dna repair mechanisms and enzymatic glycosylation across all publications each year (not limited to Nature Index journals).

Technical terms

Base excision repair (BER): A conserved DNA repair pathway that removes damaged bases via glycosylase-initiated excision and subsequent processing of the resulting abasic site.

DNA glycosylase: An enzyme that recognises and excises specific altered or mismatched bases by cleaving the N-glycosidic bond, generating an abasic site.

Base flipping: A conformational mechanism in which the target base is rotated out of the DNA helix into an enzyme’s active site for excision.

Abasic site: A deoxyribose sugar in DNA lacking its base, formed after glycosylase activity and requiring endonuclease processing.

Substrate flexibility: The intrinsic dynamic movements of DNA around a lesion that influence enzyme binding, base flipping and catalytic efficiency.

References

1. Repair and DNA Polymerase Bypass of Clickable Pyrimidine Nucleotides. Biomolecules (2024).
2. Structure of a DNA Glycosylase Bound to a Nicked T:G Mismatch-Containing DNA. Molecules (2025).
3. Uracil-DNA glycosylase efficiency is modulated by substrate rigidity. Scientific Reports (2023).
4. Excision of 5-hydroxymethyluracil and 5-carboxylcytosine by the thymine DNA glycosylase domain: its structural basis and implications for active DNA demethylation. Nucleic Acids Research (2012).