# Redox-Guided DNA Scanning by the Dynamic Repair Enzyme Endonuclease III

## TL;DR

This study explores how a DNA repair enzyme uses a redox-sensitive cluster to interact with DNA, influencing its repair activity.

## Contribution

The study reveals how the redox state of a [4Fe4S] cluster affects Endonuclease III's DNA binding and repair function.

## Key findings

- The [4Fe4S] cluster's oxidized state is stabilized near DNA, affecting enzyme binding.
- Machine learning models predicted enzyme-DNA binding distances from spectral data.
- Electrochemical stabilization correlates with EndoIII's DNA repair activity.

## Abstract

Endonuclease III
(EndoIII), a key enzyme in the base excision repair
(BER) pathway, contains a [4Fe4S] cluster that facilitates DNA repair
through DNA-mediated charge transfer. Recent findings indicate that
the redox state of this cluster influences EndoIII’s binding
affinity for DNA, modulating the enzyme’s activity. In this
study, we investigated the structural and electronic changes of the
[4Fe4S] cluster upon binding to double-stranded DNA (dsDNA) using
Fourier transform infrared spectroscopy, density functional theory
calculations, and machine learning models. Our results reveal shifts
in Fe–S bond vibrational modes, suggesting stabilization of
the oxidized [4Fe4S] cluster in proximity to negatively charged DNA.
A machine learning model, trained on the spectral features of the
EndoIII/DNA complex, predicted the enzyme-DNA binding distance, providing
further insights into the structural changes upon binding. We correlated
the electrochemical stabilization potential of 150 mV in the [4Fe4S]
cluster with the enzyme’s DNA-binding properties, demonstrating
how the cluster’s redox state plays a crucial role in both
structural stability and DNA repair.