Aretz Jonas, Jeyasankar Gayathri, Salerno-Kochan Anna, Thomsen Maren, Thieulin-Pardo Gabriel, Haque Tasir, Monteagudo Edith, Felsenfeld Dan, Finley Michael, Vogt Thomas F, Boudet Julien, Prasad Brinda C
Proteros biostructures GmbH, Bunsenstr. 7a, D - 82152, Martinsried, Germany.
CHDI Management, Inc, the company that manages the scientific activities of CHDI Foundation, Inc., Princeton, NJ, 08540, USA.
Nat Commun. 2025 May 14;16(1):4412. doi: 10.1038/s41467-025-59324-x.
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.
FAN1是一种参与DNA和链间交联修复的核酸内切酶和核酸外切酶。对亨廷顿舞蹈症患者进行的全基因组关联研究表明，FAN1基因R507H突变与疾病早期发作之间存在强关联，然而其潜在机制仍不清楚。此前有研究表明FAN1以PCNA依赖的方式调节三联体重复序列的扩增。为了研究PCNA对FAN1激活的作用，我们解析了PCNA-FAN1-DNA复合物的冷冻电镜结构。我们的研究结果表明，FAN1的R507残基直接与PCNA的D232相互作用。生物物理相互作用研究表明，FAN1增强了PCNA与DNA的结合亲和力，而携带R507H突变的突变体中这种协同效应被破坏。相反，PCNA不影响FAN1与DNA的亲和力，但在三元复合物形成时调节FAN1的活性。功能减弱且发生改变的FAN1 R507H-PCNA-DNA复合物可能部分损害FAN1介导的CAG螺旋外突出的修复，这为该突变在加速疾病进展中的作用提供了一个潜在解释。
