Trasviña-Arenas CH et al., Nature Communications - This episode explores a 2025 study that reports the first human MUTYH structure bound to a transition state analog and functional profiling of cancer-associated variants near its [4Fe-4S] cluster. The authors map an evolutionarily conserved hydrogen-bond network linking the metal cluster to the catalytic Asp236 and show how specific variants disrupt catalysis. Two variants (R241Q, N238S) retain metal binding and DNA affinity yet lose glycosylase activity, revealing an allosteric regulatory role for the cofactor. Molecular dynamics and a bacterial homolog structure support a model in which the cluster positions and modulates the catalytic residue to enable adenine excision. Key terms: MUTYH, 4Fe-4S cluster, base excision repair, allosteric network, cancer-associated variants.

Study Highlights:
Researchers solved a 1.9 Å human MUTYH–transition state analog crystal structure that uncovers a hydrogen-bond bridge from the [4Fe-4S] cluster to the active site. Functional profiling of 12 cancer-associated variants near the cluster shows most lose cofactors and activity, while R241Q and N238S uniquely retain metals and DNA binding but are inactive. A corresponding bacterial R149Q structure and molecular dynamics reveal alternate cluster conformations and altered dynamics that disrupt communication to catalytic Asp236. Together the data support an allosteric network that positions and affects the protonation state of Asp236 to enable base excision.

Conclusion:
The [4Fe-4S] cluster in MUTYH is an active allosteric element connected to the catalytic pocket via a conserved Cys290–Arg241–Asn238–Asp236 hydrogen-bond network; disruption of this bridge by cancer-associated variants can disable DNA repair even when metal binding and DNA affinity are retained, highlighting a mechanism for MUTYH-associated mutagenesis and a potential regulatory or therapeutic target.

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-04-19.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 8
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- There is a 20 Å hydrogen-bond network bridging the [4Fe-4S] cluster to the active site, connecting Cys290–Arg241–Asn238–Asp236 to position and modulate Asp236 for base excision.
- Crystal structure of human MUTYH with DNA bound (MUTYH-TSAC) demonstrates the bridge between the [4Fe-4S] cluster and active site, supporting allosteric cross-talk.
- R241Q and N238S cancer-associated variants retain metal cofactor and DNA binding yet are catalytically inactive, illustrating allosteric disruption without global unfolding.
- Most cancer-associated variants near the [4Fe-4S] cluster disrupt metal cofactors and cause loss of activity; exceptions (R241Q/N238S) retain metal/DNA binding but are inactive.
- The allosteric network is evolutionarily conserved across MUTYH and related HhH BER glycosylases (e.g., MIG, EndoIII).
- Under oxidative stress, oxidation state changes of the [4Fe-4S] cluster act as an environmental sensor that down-regulates MUTYH to prevent catastrophic genome fragmentation.

QC result: Pass.