ArticleNature communications2025
Structure of human MUTYH and functional profiling of cancer-associated variants reveal an allosteric network between its [4Fe-4S] cluster cofactor and active site required for DNA repair.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- Effects of a cancer-associated mutation and multiple serine phosphorylation on poly(ADP-ribose) polymerase 2.Biophysical journal · 2026Article
- DNA Damage Recognition by Bacterial and Human Adenine-DNA Glycosylases: Insights from Non-Canonical Substrates.Biomolecules · 2026Article
- MUTYH Cancer-Associated Variants Within the Interdomain Connector Differentially Impact Glycosylase Activity and Cellular DNA Repair.Chembiochem : a European journal of chemical biology · 2026Article
- 8oxoG:A Is Structurally Accommodated in the Nucleosome Core Particle, Yet Inaccessible to MUTYH-Initiated DNA Repair.Biomolecules · 2026Article
- Biochemical, structural and mutational landscapes of base excision repair enzymes and cancer: from atomic resolution to tumor signatures.International journal of radiation biology · 2026Review
- Structural Basis for Nucleobase Activation by the Adenine DNA Glycosylase MutY.Chembiochem : a European journal of chemical biology · 2026Article
- Facilitated DNA damage repair as an emerging therapeutic strategy for inflammatory and fibrotic diseases.RSC chemical biology · 2026Review
- Regulatory networks of iron sulfur cluster biology in cancer mechanisms and therapeutic perspectives.iScience · 2026Review
- OGG1 and MUTYH DNA Glycosylases, the Dynamic Duo Against 8-Oxoguanine DNA Lesion: Structure, Regulation, and Novel Emerging Roles.Biomolecules · 2026Review
- Structural Basis for Nucleobase Activation by the Adenine DNA Glycosylase MutY.bioRxiv : the preprint server for biology · 2026Article
- Crystal structure of MutYX: a novel clusterless adenine DNA glycosylase with a distinct C-terminal domain and 8-oxoguanine recognition sphere.Nucleic acids research · 2025Article
- Comparison of Magnesium and Manganese Ions on the Structural and Catalytic Properties of Human DNA Polymerase Gamma.Journal of chemical theory and computation · 2025Article
- Saturation mapping of MUTYH variant effects using DNA repair reporters.American journal of human genetics · 2025Article
- Computational studies on the functional and structural impact of pathogenic mutations in enzymes.Protein science : a publication of the Protein Society · 2025Review
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Authors and funding
11 authors.
Funding
Abstract
MUTYH is a clinically important DNA glycosylase that thwarts mutations by initiating base-excision repair at 8-oxoguanine (OG):A lesions. The roles for its [4Fe-4S] cofactor in DNA repair remain enigmatic. Functional profiling of cancer-associated variants near the [4Fe-4S] cofactor reveals that most variations abrogate both retention of the cofactor and enzyme activity. Surprisingly, R241Q and N238S retained the metal cluster and bound substrate DNA tightly, but were completely inactive. We determine the crystal structure of human MUTYH bound to a transition state mimic and this shows that Arg241 and Asn238 build an H-bond network connecting the [4Fe-4S] cluster to the catalytic Asp236 that mediates base excision. The structure of the bacterial MutY variant R149Q, along with molecular dynamics simulations of the human enzyme, support a model in which the cofactor functions to position and activate the catalytic Asp. These results suggest that allosteric cross-talk between the DNA binding [4Fe-4S] cofactor and the base excision site of MUTYH regulate its DNA repair function.
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