Redox signaling between DNA repair proteins for efficient lesion detection

  • Boal A
  • Genereux J
  • Sontz P
 et al. 
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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.

Author-supplied keywords

  • 8-oxoguanine
  • DNA charge transport
  • DNA damage
  • base-excision-repair
  • crystal-structure
  • enzyme endonuclease-iii
  • escherichia-coli
  • glycosylase
  • in-vivo
  • iron-sulfur proteins
  • mediated charge-transport
  • muty
  • oxidative damage
  • oxidative stress

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Authors

  • A K Boal

  • J C Genereux

  • P A Sontz

  • J A Gralnick

  • D K Newman

  • J K Barton

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