A human MUTYH variant linking colonic polyposis to redox degradation of the [4Fe4S]2+ cluster

Kevin J. McDonnell, Joseph A. Chemler, Phillip L. Bartels, Elizabeth O’Brien, Monica L. Marvin, Janice Ortega, Ralph H. Stern, Leon Raskin, Guo Min Li, David H. Sherman, Jacqueline K. Barton, Stephen B. Gruber

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1-8
Number of pages8
JournalNature Chemistry
DOIs
StateAccepted/In press - Jun 18 2018

Fingerprint

DNA
Degradation
DNA Repair Enzymes
Electrochemistry
Adenine
Tryptophan
Cysteine
Repair
Enzymes
Oxidation-Reduction
Proteins

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)

Cite this

McDonnell, K. J., Chemler, J. A., Bartels, P. L., O’Brien, E., Marvin, M. L., Ortega, J., ... Gruber, S. B. (Accepted/In press). A human MUTYH variant linking colonic polyposis to redox degradation of the [4Fe4S]2+ cluster. Nature Chemistry, 1-8. https://doi.org/10.1038/s41557-018-0068-x

A human MUTYH variant linking colonic polyposis to redox degradation of the [4Fe4S]2+ cluster. / McDonnell, Kevin J.; Chemler, Joseph A.; Bartels, Phillip L.; O’Brien, Elizabeth; Marvin, Monica L.; Ortega, Janice; Stern, Ralph H.; Raskin, Leon; Li, Guo Min; Sherman, David H.; Barton, Jacqueline K.; Gruber, Stephen B.

In: Nature Chemistry, 18.06.2018, p. 1-8.

Research output: Contribution to journalArticle

McDonnell, KJ, Chemler, JA, Bartels, PL, O’Brien, E, Marvin, ML, Ortega, J, Stern, RH, Raskin, L, Li, GM, Sherman, DH, Barton, JK & Gruber, SB 2018, 'A human MUTYH variant linking colonic polyposis to redox degradation of the [4Fe4S]2+ cluster', Nature Chemistry, pp. 1-8. https://doi.org/10.1038/s41557-018-0068-x
McDonnell, Kevin J. ; Chemler, Joseph A. ; Bartels, Phillip L. ; O’Brien, Elizabeth ; Marvin, Monica L. ; Ortega, Janice ; Stern, Ralph H. ; Raskin, Leon ; Li, Guo Min ; Sherman, David H. ; Barton, Jacqueline K. ; Gruber, Stephen B. / A human MUTYH variant linking colonic polyposis to redox degradation of the [4Fe4S]2+ cluster. In: Nature Chemistry. 2018 ; pp. 1-8.
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