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bioRxiv · 10.1101/2024.10.07.617005

Structural and molecular basis of FAN1 defects in promoting Huntington's disease

Pluciennik, A.·Li, F.·Phadte, A. A.·Bhatia, M.·Barndt, S.·Monte Carlo, A. R.·Hou, C.-f. D.·Yang, R.·Strock, S.
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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 Huntingtons 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 on a disease-relevant extrahelical DNA extrusions formed within DNA repeats. This mutation concomitantly abolishes PCNA-FAN1-dependent cleavage of such extrusions, underscoring the importance of PCNA to the genome stabilizing function of FAN1. These results unravel the molecular basis for a specific mutation in FAN1 that dramatically hastens the onset of Huntingtons disease.

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Pluciennik, A., Li, F., Phadte, A. A., Bhatia, M., Barndt, S., Monte Carlo, A. R., Hou, C.-f. D., Yang, R., Strock, S.. 2024-10-07. Structural and molecular basis of FAN1 defects in promoting Huntington's disease. https://doi.org/10.1101/2024.10.07.617005

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