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.
Show 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.
Matching journals
The top 2 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Structural basis for Lamassu-based antiviral immunity and its evolution from DNA repair machinery 98%
- Mix-and-inject XFEL crystallography reveals gated conformational dynamics during enzyme catalysis 98%
- In situ structural analysis reveals membrane shape transitions during autophagosome formation 97%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.