Cadmium inhibits hSMUG1-mediated uracil excision: quantitative analysis and mitigation by Ganoderma lucidum extracts

Cadmium is a pervasive environmental carcinogen known to disrupt multiple DNA repair pathways, yet its direct impact on uracil base excision repair enzyme activity remains unclear. Here, we quantitatively demonstrate that cadmium potently inhibits hSMUG1, a key enzyme initiating removal of mutagenic U:G mispairs arising from cytosine deamination. Using a nucleotide-resolution MALDI-TOF mass spectrometry assay, we show that cadmium suppresses hSMUG1 activity in a dose-dependent manner (IC₅₀ = 4.6 μM), with near-complete inhibition at concentrations ≥25 μM. Notably, five Ganoderma lucidum extracts derived from different strains and extraction methods restored hSMUG1 activity (16.4-21.6%) under cadmium stress. ICP mass spectrometry revealed that these extracts reduced cadmium ion levels by 40-73%, suggesting metal chelation as a contributing mechanism. Together, our findings uncover a previously unrecognised mechanism by which cadmium compromises base excision repair and establishes a robust framework for evaluating environmental metal toxicity and its modulation at single-nucleotide resolution.