9CHM

Cryo-EM structure of FAN1 R507H and PCNA in intermediate state

9CHM の概要

• エントリーDOI: 10.2210/pdb9chm/pdb
• EMDBエントリー: 45590
• 分子名称: Fanconi-associated nuclease 1, Proliferating cell nuclear antigen (2 entities in total)
• 機能のキーワード: nuclease, cag expansion, dna repair, huntington's disease, dna binding protein, protein binding
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 107322.75

構造登録者

Li, F.,Pluciennik, A. (登録日: 2024-07-01, 公開日: 2025-02-19, 最終更新日: 2025-09-03)

主引用文献

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

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: 40368897
DOI: 10.1038/s41467-025-59323-y

実験手法

ELECTRON MICROSCOPY (3.47 Å)