Toxicant-Induced Repair Drift: How arsenic and organophosphates push DSB repair toward error-prone routes via zinc-finger disruption and chromatin ubiquitination

Arsenic binds/oxidizes zinc-finger proteins and disrupts repair (Tam et al., 2020), while organophosphates induce DNA damage and modulate repair capacity (Prathiksha et al., 2023). SHPRH, a RAD5-like factor, is a nucleosome-stimulated ATPase and E3 ligase that ubiquitinates PCNA and nucleosomes in distinct linkages (Brühl et al., 2019). The hypothesis is that arsenic/organophosphates impair zinc-finger DDR hubs (e.g., XPA scaffolding in NER) and rewire SHPRH-driven chromatin ubiquitination, biasing lesion bypass and DSB repair toward MMEJ/SSA. The approach uses exposure-controlled cell systems and chromatin-ubiquitin linkage proteomics, PCNA-ubiquitin dynamics, and pathway reporters; correlating with resultant mutational spectra via duplex/long-read sequencing. This integrates toxicology with chromatin-centric repair regulation and clinically relevant NER scaffolding, incorporating pathway hierarchy concepts. Identifying “repair drift” as an exposure-driven phenomenon could explain exposure-specific cancer mutation patterns and inform interventions such as antioxidants targeting zinc-finger oxidation or E3 ligase modulators. The impact is a mechanistic basis for environmental mutagenesis patterns and rational strategies to mitigate carcinogenic risk through pathway steering.

References:

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