Abstract

The human DNA repair enzyme MUTYH excises mispaired adenine residues in oxidized DNA. Homozygous MUTYH mutations underlie the autosomal, recessive cancer syndrome MUTYH-associated polyposis. We report a MUTYH variant, p.C306W (c.918C>G), with a tryptophan residue in place of native cysteine, that ligates the [4Fe4S] cluster in a patient with colonic polyposis and family history of early age colon cancer. In bacterial MutY, the [4Fe4S] cluster is redox active, allowing rapid localization to target lesions by long-range, DNA-mediated signalling. In the current study, using DNA electrochemistry, we determine that wild-type MUTYH is similarly redox-active, but MUTYH C306W undergoes rapid oxidative degradation of its cluster to [3Fe4S]+, with loss of redox signalling. In MUTYH C306W, oxidative cluster degradation leads to decreased DNA binding and enzyme function. This study confirms redox activity in eukaryotic DNA repair proteins and establishes MUTYH C306W as a pathogenic variant, highlighting the essential role of redox signalling by the [4Fe4S] cluster.

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Acknowledgements

The authors thank T. Huston of the W.M. Keck Lab in the Department of Earth & Environmental Sciences at the University of Michigan for ICP-HRMS analyses. This work was funded in part by a Ruth L. Kirschstein National Research Service Award (GM095065 to J.A.C.), a National Institutes of Health (NIH) grant (R35 GM118101) and an H.W. Vahlteich Professorship (to D.H.S.), a Ruth L. Kirschstein National Research Service Award and American Society of Clinical Oncology Young Investigator Award (to K.M.), grant 1R01CA197350 (to S.B.G.), a USC Norris Comprehensive Cancer Center Support Grant (CA014089 to S.B.G.), an award from the Ming Hsieh Institute for Engineering—Medicine for Cancer, and support from Daniel and Maryann Fong and the Anton B. Burg Foundation (to S.B.G.). P.L.B., E.O.B. and J.K.B. acknowledge the NIH (GM126904 to J.K.B.) and Moore Foundation for financial support. E.O.B. acknowledges NIH training grant T32-GM07616 and a Ralph Parsons Fellowship for support.

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Author notes

  1. These authors contributed equally to this work: Kevin J. McDonnell, Joseph A. Chemler, Phillip L. Bartels.

Affiliations

  1. University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA

    • Kevin J. McDonnell
    •  & Stephen B. Gruber
  2. Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA

    • Joseph A. Chemler
    •  & David H. Sherman
  3. Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA

    • Phillip L. Bartels
    • , Elizabeth O’Brien
    •  & Jacqueline K. Barton
  4. Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA

    • Monica L. Marvin
  5. Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    • Janice Ortega
    •  & Guo-Min Li
  6. Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    • Ralph H. Stern
  7. Amgen Inc., Thousand Oaks, CA, USA

    • Leon Raskin
  8. Departments of Medicinal Chemistry, Chemistry and Microbiology & Immunology, University of Michigan, Ann Arbor, MI, USA

    • David H. Sherman

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Contributions

K.M., J.C., P.B., E.O., D.S., J.B. and S.G. conceived and designed the experiments. K.M., J.C. and P.B. co-wrote the paper with input from all authors. R.S., L.R., M.M., J.O. and G.L. contributed materials and analysis tools. K.M., J.C. and P.B. performed the experiments.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to David H. Sherman or Jacqueline K. Barton or Stephen B. Gruber.

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https://doi.org/10.1038/s41557-018-0068-x