Strock, S. | Search bioRxiv

bioRxiv2024

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

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.

biochemistry↗

bioRxiv2023

Nectophore coordination and kinematics by physonect siphonophores

Siphonophores are ubiquitous and often highly abundant members of pelagic ecosystems throughout the open ocean. They are unique among animal taxa in that they use multiple jets for propulsion. Little is known about kinematics of the individual jets produced by nectophores or how the jets are coordinated during normal swimming behavior. Using remotely operated vehicles and SCUBA, we video recorded the swimming behavior of several physonect species in their natural environment. The pulsed kinematics of the individual nectophores that comprise the siphonophore nectosome were quantified and, based on these kinematics, we examined the coordination of adjacent nectophores. We found for all species that nectophores sharing the same side of the nectosomal axis were coordinated metachronally. However, this coordination was not shared with nectophores on the opposite side of the nectosomal axis. For most species, the metachronal contraction waves of nectophores were initiated by the apical nectophores and traveled dorsally. However, the metachronal wave of Apolemia rubriversa traveled in the opposite direction. Although nectophore groups on opposite sides of the nectosome were not coordinated, they pulsed with similar frequencies. This enabled siphonophores to maintain relatively linear trajectories during swimming. The timing and characteristics of the metachronal coordination of pulsed jets affects how the jet wakes interact and may provide important insight into how interacting jets may be optimized for efficient propulsion.

zoology↗