Document Type
Article
Publication Date
5-14-2025
Abstract
FAN1 is a DNA dependent nuclease whose proper function is essential for maintaining human health. For example, a genetic variant in FAN1, Arg507 to His hastens onset of Huntington's disease, a repeat expansion disorder for which there is no cure. How the Arg507His mutation affects FAN1 structure and enzymatic function is unknown. Using cryo-EM and biochemistry, we have discovered that FAN1 arginine 507 is critical for its interaction with PCNA, and mutation of Arg507 to His attenuates assembly of the FAN1-PCNA complex on a disease-relevant extrahelical DNA extrusions formed within DNA repeats. This mutation concomitantly abolishes PCNA-FAN1-dependent cleavage of such extrusions, thus unraveling the molecular basis for a specific mutation in FAN1 that dramatically hastens the onset of Huntington's disease. These results underscore the importance of PCNA to the genome stabilizing function of FAN1.
Recommended Citation
Li, F.; Phadte, A. S.; Bhatia, M.; Barndt, S.; Monte Carlo, III, A.R.; Hou, C.F.D.; Yang, R.; Strock, S.; and Pluciennik, A., "Structural and Molecular Basis of PCNA-Activated FAN1 Nuclease Function in DNA Repair" (2025). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 282.
https://jdc.jefferson.edu/bmpfp/282
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Description of Additional Supplementary Files.pdf (11 kB)
Supplementary Data 1.xlsx (10 kB)
Supplementary Data 2.xlsx (14 kB)
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PubMed ID
40368897
Language
English
Comments
This article is the author’s final published version in Nature Communications, Volume 16, 2025, Article number 4411.
The published version is available at https://doi.org/10.1038/s41467-025-59323-y. Copyright © The Author(s) 2025.