Redox signaling between DNA repair proteins for efficient lesion detection

Amie K. Boal, Joseph C. Genereux, Pamela A. Sontz, Jeffrey A. Gralnick, Dianne K. Newman, Jacqueline K. Barton

Research output: Contribution to journalArticlepeer-review

116 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)15237-15242
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number36
StatePublished - Sep 8 2009

All Science Journal Classification (ASJC) codes

  • General


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