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Structural and molecular basis of PCNA-activated FAN1 nuclease function in DNA repair
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Structural and molecular basis of PCNA-activated FAN1 nuclease function in DNA repair
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Journal Article
Structural and molecular basis of PCNA-activated FAN1 nuclease function in DNA repair
2025
Overview
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.
FAN1 nuclease removes DNA triplet repeat loops by a process that requires PCNA. Using cryo-EM, the authors elucidate this mechanism, and show that a Huntington’s disease modifying R507H mutation inactivates FAN1 by compromising the FAN1-PCNA complex.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13
/ 82/80
/ 82/83
/ DNA
/ Endodeoxyribonucleases - chemistry
/ Endodeoxyribonucleases - genetics
/ Endodeoxyribonucleases - metabolism
/ Exodeoxyribonucleases - chemistry
/ Exodeoxyribonucleases - genetics
/ Exodeoxyribonucleases - metabolism
/ Exodeoxyribonucleases - ultrastructure
/ Humanities and Social Sciences
/ Humans
/ Huntington Disease - genetics
/ Huntington Disease - metabolism
/ Multifunctional Enzymes - chemistry
/ Multifunctional Enzymes - genetics
/ Multifunctional Enzymes - metabolism
/ Mutation
/ Nuclease
/ Proliferating cell nuclear antigen
/ Proliferating Cell Nuclear Antigen - chemistry
/ Proliferating Cell Nuclear Antigen - genetics
/ Proliferating Cell Nuclear Antigen - metabolism
/ Science
