236: XPD translocation and genetic disease etiology

Paul T et al., Nat Commun - Computational modeling reveals how ATP-driven conformational cycles of the XPD helicase drive directional 5′→3′ translocation on single-stranded DNA and how mutations disrupt this process to cause disease. Key terms: XPD, DinG, ssDNA translocation, nucleotide excision repair, disease mutations. Study Highlights: The authors combined molecular dynamics, partial nudged elastic band path optimization, transition path sampling, and Markov state modeling to map seven metastable on-path states that define XPD’s ATPase cycle. ATP binding and hydrolysis drive reciprocal rotations of the RecA2 and Arch domains, transmitted via a spring helix and spindle helix, that alternate DNA affinity at two defined constrictions at the 5′ and 3′ ends of the DNA-binding groove. Translocation proceeds in two phases: RecA2-driven sliding of ssDNA through Constriction 1 followed by ATP hydrolysis, constriction switching and sliding through Constriction 2, advancing one nucleotide per ATP. Mapping of missense mutations shows clustering of disease-associated residues at DNA- and ATP-binding sites and classifies mutations that impair DNA binding, ATPase function, or allosteric domain dynamics Conclusion: A detailed mechanistic map links XPD’s nucleotide-dependent conformational switching to directional ssDNA translocation and explains how perturbations of key residues underlie XP, CS, and TTD phenotypes Music: Enjoy the music based on this article at the end of the episode. Article title: Translocation mechanism of xeroderma pigmentosum group D protein on single-stranded DNA and genetic disease etiology First author: Paul T Journal: Nat Commun DOI: 10.1038/s41467-025-66834-1 Reference: Paul T, Yan C, Derdeyn-Blackwell G, Ivanov I. Translocation mechanism of xeroderma pigmentosum group D protein on single-stranded DNA and genetic disease etiology. Nat Commun. 2025. https://doi.org/10.1038/s41467-025-66834-1 License: This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support: Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/xpd-translocation-disease-etiology QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-12-22. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited transcript portions describing XPD’s translocation mechanism, the seven-state ATPase cycle (S1–S7), the roles of Constriction 1 and Constriction 2, mutation class mapping to XP/CS/TTD phenotypes, XPD–DinG comparison, and per-nucleotide kinetic estimates. - transcript topics: XPD function in nucleotide excision repair and lesion verification; XPD domain architecture and DNA-binding groove; Seven-state ATPase cycle (S1–S7) and translocation on ssDNA; Constriction 1 (5′ end) and Constriction 2 (3′ end) as molecular clamps; ATP binding/hydrolysis and mechanical coupling (spring spindle helix, Arch/Fe–S interactions); Disease mutations: XP, CS, TTD phenotypes and class mapping QC Summary: - factual score: 10/10 - metadata score: 10/10 - supported core claims: 7 - 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: - XPD translocates 5′... Chapters (00:00:14) - Leading the charge in the DNA repair process (00:04:33) - How XPD moves forward in the DNA (00:07:49) - How does XPD pull the DNA forward? (00:10:36) - How XPCS mutations disrupt the ATP engine (00:12:46) - XPD