Correlation between Charge Transport and Base Excision Repair in the MutY-DNA Glycosylase.

Area of Science:

• Biochemistry
• Molecular Biology
• Bioinorganic Chemistry

Background:

• DNA replication and repair involve redox signaling mediated by high-potential iron-sulfur ([Fe4S4]) proteins.
• Protein-mediated charge transfer (CT) between [Fe4S4] clusters and nucleic acids is crucial for these biological processes.

Purpose of the Study:

• To analyze the dominant charge transfer pathways in the base excision repair glycosylase MutY.
• To investigate the role of the adenine nucleobase in mismatched DNA base pairs during CT.
• To assess the impact of the R153L mutation on MutY's CT pathways and rates.

Main Methods:

• Molecular dynamics simulations were employed to model MutY-DNA interactions.
• Hole hopping pathway analysis was used to identify dominant CT routes.
• The influence of the R153L mutation on CT pathways and rates was quantitatively assessed.

Main Results:

• The adenine nucleobase of an A·oxoG mismatched DNA base pair was found to facilitate [Fe4S4]-DNA CT before adenine excision by MutY.
• The R153L mutation was shown to alter the preferred CT pathways within MutY.
• This mutation significantly reduced the effective charge transfer rates.

Conclusions:

• MutY utilizes DNA-mediated redox signaling for base excision repair.
• The adenine nucleobase plays a key role in initiating charge transfer.
• The R153L mutation impairs MutY function by disrupting efficient charge transfer, with implications for colorectal adenomatous polyposis.