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TitleStructural and molecular basis of PCNA-activated FAN1 nuclease function in DNA repair.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 4411, Year 2025
Publish dateMay 14, 2025
AuthorsF Li / A S Phadte / M Bhatia / S Barndt / A R Monte Carlo Iii / C-F D Hou / R Yang / S Strock / A Pluciennik /
PubMed AbstractFAN1 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 ...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.
External linksNat Commun / PubMed:40368897 / PubMed Central
MethodsEM (single particle)
Resolution3.37 - 3.97 Å
Structure data

45568

9cg4

EMDB-45568, PDB-9cg4:
Cryo-EM structure of FAN1, PCNA and DNA substrate with (CAG)2 extrusion in intermediate state
Method: EM (single particle) / Resolution: 3.37 Å

45590

9chm

EMDB-45590, PDB-9chm:
Cryo-EM structure of FAN1 R507H and PCNA in intermediate state
Method: EM (single particle) / Resolution: 3.47 Å

45664

9cl7

EMDB-45664, PDB-9cl7:
Cryo-EM structure of FAN1-PCNA-DNA in final state
Method: EM (single particle) / Resolution: 3.83 Å

45745

9cma

EMDB-45745, PDB-9cma:
Cryo-EM structure of FAN1 R507H-PCNA-DNA in final state
Method: EM (single particle) / Resolution: 3.97 Å

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsDNA BINDING PROTEIN / nuclease / CAG expansion / DNA repair / Huntington's disease / PROTEIN BINDING

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