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TitleA FAN1 point mutation associated with accelerated Huntington's disease progression alters its PCNA-mediated assembly on DNA.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 4412, Year 2025
Publish dateMay 14, 2025
AuthorsJonas Aretz / Gayathri Jeyasankar / Anna Salerno-Kochan / Maren Thomsen / Gabriel Thieulin-Pardo / Tasir Haque / Edith Monteagudo / Dan Felsenfeld / Michael Finley / Thomas F Vogt / Julien Boudet / Brinda C Prasad /
PubMed AbstractFAN1 is an endo- and exo-nuclease involved in DNA and interstrand crosslink repair. Genome-wide association studies of people with Huntington's disease revealed a strong association between the FAN1 ...FAN1 is an endo- and exo-nuclease involved in DNA and interstrand crosslink repair. Genome-wide association studies of people with Huntington's disease revealed a strong association between the FAN1 R507H mutation and early disease onset, however the underlying mechanism(s) remains unclear. FAN1 has previously been implicated in modulating triplet repeat expansion in a PCNA dependent manner. To examine the role of PCNA on FAN1 activation, we solved the cryo-EM structures of a PCNA-FAN1-DNA complex. Our findings reveal that the FAN1 R507 residue directly interacts with PCNA D232. Biophysical interaction studies demonstrated that FAN1 enhances the binding affinity of PCNA for DNA, a synergistic effect disrupted in mutants carrying the R507H mutation. In contrast, PCNA does not affect the affinity of FAN1 for DNA but does modulate FAN1 activity upon ternary complex formation. The weakened and functionally altered FAN1 R507H-PCNA-DNA complex may partly impair the FAN1-mediated repair of CAG extrahelical extrusions, providing a potential explanation for the mutation's role in accelerating disease progression.
External linksNat Commun / PubMed:40368883 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.645 - 3.42 Å
Structure data

19844

9eo1

EMDB-19844, PDB-9eo1:
Cryo_EM structure of human FAN1 in complex with 5' flap DNA substrate
Method: EM (single particle) / Resolution: 3.2 Å

19850

9eoa

EMDB-19850, PDB-9eoa:
Cryo_EM structure of human FAN1 in complex with 5' flap DNA substrate and PCNA
Method: EM (single particle) / Resolution: 3.27 Å

51680

9gy0

EMDB-51680, PDB-9gy0:
Cryo_EM structure of human FAN1 R507H mutant in complex with 5' flap DNA substrate and PCNA
Method: EM (single particle) / Resolution: 3.42 Å

PDB-8s5a:
The crystal structure of FAN1 Nuclease bound to 5' phosphorylated p(dG)/3'(dT-dT-dT-dT) double flap DNA
Method: X-RAY DIFFRACTION / Resolution: 2.645 Å

Chemicals

ChemComp-CA:
Unknown entry

ChemComp-CL:
Unknown entry

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsDNA / nuclease FAN1 / DNA BINDING PROTEIN / FAN1 / PCNA / FAN1 R507H

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