Structural and molecular basis of PCNA-activated FAN1 nuclease function in DNA repair

F. Li, A. S. Phadte, M. Bhatia, S. Barndt, A. R. Monte Carlo, C-F. D. Hou, R. Yang, S. Strock and A. Pluciennik ()
Additional contact information
F. Li: Thomas Jefferson University
A. S. Phadte: Thomas Jefferson University
M. Bhatia: Thomas Jefferson University
S. Barndt: Thomas Jefferson University
A. R. Monte Carlo: Thomas Jefferson University
C-F. D. Hou: Thomas Jefferson University
R. Yang: Princeton University
S. Strock: Thomas Jefferson University
A. Pluciennik: Thomas Jefferson University

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59323-y

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