Translocation mechanism of xeroderma pigmentosum group D protein on single-stranded DNA and genetic disease etiology
Year: 2025
Type: article
Abstract: XPD is a key nucleotide excision repair (NER) protein whose function is vital for genome integrity. During NER, XPD serves as a 5'-3' single-strand DNA translocase that enables lesion scanning and verification in genomic DNA. Yet, its translocation mechanism is incompletely understood. Here we use molecular simulations and chain-of-replicas path optimization methods to model the ATP-driven translocation mechanisms of XPD and its bacterial homolog DinG, revealing all on-path metastable intermediates and corresponding kinetic rates. We identify the XPD(DinG) global domain motions that modulate the strength of DNA association at the opposing ends of the DNA-binding groove. During the ATP hydrolysis cycle, alternating weak and strong interactions at two defined groove constrictions enable DNA reptation and forward displacement of the ATPase. Moreover, we show that DNA- or ATP-binding residues directly involved in translocation are hotspots for genetic disease mutations. Thus, our findings shed light on the etiology of XPD-associated genetic syndromes.
Source: Nature Communications
Institution: Georgia State University
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: G1054907967, G1300000038, Integrative Modeling of Biomolecular Machinery in Nucleotide Excision Repair, G2149942465, G2680263196, Structural Cell Biology of DNA Repair Machines, G3999884092, G4757340005, Advanced Computational Modeling of Molecular Machines in Gene Regulation and DNA Repair, G5687242219, Advanced Computational Modeling of Pathways for Epigenetic Regulation and Genome Maintenance, G88713976
OpenAlex ID: W4416791447