9CHM
Cryo-EM structure of FAN1 R507H and PCNA in intermediate state
Summary for 9CHM
| Entry DOI | 10.2210/pdb9chm/pdb |
| EMDB information | 45590 |
| Descriptor | Fanconi-associated nuclease 1, Proliferating cell nuclear antigen (2 entities in total) |
| Functional Keywords | nuclease, cag expansion, dna repair, huntington's disease, dna binding protein, protein binding |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 107322.75 |
| Authors | Li, F.,Pluciennik, A. (deposition date: 2024-07-01, release date: 2025-02-19, Last modification date: 2025-09-03) |
| Primary citation | Li, F.,Phadte, A.S.,Bhatia, M.,Barndt, S.,Monte Carlo Iii, A.R.,Hou, C.D.,Yang, R.,Strock, S.,Pluciennik, A. Structural and molecular basis of PCNA-activated FAN1 nuclease function in DNA repair. Nat Commun, 16:4411-4411, 2025 Cited by PubMed 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. PubMed: 40368897DOI: 10.1038/s41467-025-59323-y PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.47 Å) |
Structure validation
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