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

McDonnell, Kevin J. and Chemler, Joseph A. and Bartels, Phillip L. and O'Brien, Elizabeth and Marvin, Monica L. and Ortega, Janice and Stern, Ralph H. and Raskin, Leon and Li, Guo-Min and Sherman, David H. and Barton, Jacqueline K. and Gruber, Stephen B. (2018) A human MUTYH variant linking colonic polyposis to redox degradation of the [4Fe4S]²⁺ cluster. Nature Chemistry, 10 (8). pp. 873-880. ISSN 1755-4330. PMCID PMC6060025. doi:10.1038/s41557-018-0068-x.

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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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URLURL TypeDescription ReadCube access CentralArticle
McDonnell, Kevin J.0000-0002-4942-8943
Li, Guo-Min0000-0002-9842-4578
Sherman, David H.0000-0001-8334-3647
Barton, Jacqueline K.0000-0001-9883-1600
Alternate Title:A human MUTYH variant linking colonic polyposis to redox degradation of the [4Fe4S]2+ cluster
Additional Information:© 2018 Macmillan Publishers Limited. Received: 18 June 2017; Accepted: 20 April 2018; Published: 18 June 2018. 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. These authors contributed equally to this work: Kevin J. McDonnell, Joseph A. Chemler, Phillip L. Bartels. Author 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. Reporting Summary: Further information on experimental design is available in the Nature Research Reporting Summary linked to this article. Data availability: The data sets generated during and/or analysed during the current study are available from the corresponding author. The authors declare no competing interests.
Funding AgencyGrant Number
NIH Predoctoral FellowshipGM095065
NIHR35 GM118101
H. W. Vahlteich ProfessorshipUNSPECIFIED
American Society of Clinical OncologyUNSPECIFIED
Ming Hsieh Institute for Engineering—Medicine for CancerUNSPECIFIED
Daniel and Maryann FongUNSPECIFIED
Anton B. Burg FoundationUNSPECIFIED
Gordon and Betty Moore FoundationUNSPECIFIED
NIH Predoctoral FellowshipT32-GM07616
Ralph M. Parsons FoundationUNSPECIFIED
Issue or Number:8
PubMed Central ID:PMC6060025
Record Number:CaltechAUTHORS:20180222-102406884
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:84920
Deposited By: George Porter
Deposited On:18 Jun 2018 20:56
Last Modified:15 Nov 2021 20:24

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