title: Redox signaling between DNA repair proteins for efficient lesion detection.
abstract: Base excision repair (BER) enzymes maintain the integrity of the genome, and in humans, BER mutations are associated with cancer. Given the remarkable sensitivity of DNA-mediated charge transport (CT) to mismatched and damaged base pairs, we have proposed that DNA repair glycosylases (EndoIII and MutY) containing a redox-active [4Fe4S] cluster could use DNA CT in signaling one another to search cooperatively for damage in the genome. Here, we examine this model, where we estimate that electron transfers over a few hundred base pairs are sufficient for rapid interrogation of the full genome. Using atomic force microscopy, we found a redistribution of repair proteins onto DNA strands containing a single base mismatch, consistent with our model for CT scanning. We also demonstrated in Escherichia coli a cooperativity between EndoIII and MutY that is predicted by the CT scanning model. This relationship does not require the enzymatic activity of the glycosylase. Y82A EndoIII, a mutation that renders the protein deficient in DNA-mediated CT, however, inhibits cooperativity between MutY and EndoIII. These results illustrate how repair proteins might efficiently locate DNA lesions and point to a biological role for DNA-mediated CT within the cell.
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Amie K
authors.initials: AK
authors.lastname: Boal
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Genereux
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Sontz
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Gralnick
authors.forename: Dianne K
authors.initials: DK
authors.lastname: Newman
authors.forename: Jacqueline K
authors.initials: JK
authors.lastname: Barton
mesh_terms: D004249:DNA Damage / Q000235:genetics*; D045647:DNA Glycosylases / Q000378:metabolism*; D004260:DNA Repair; D004579:Electron Transport; D004926:Escherichia coli; D018625:Microscopy, Atomic Force; D008954:Models, Biological; D010084:Oxidation-Reduction; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D045647:DNA Glycosylases