Poly(ADP-ribose) drives FUS condensation via a transient interaction
This article was originally published here
Mol cell. 12 February 2022: S1097-2765(22)00061-2. doi:10.1016/j.molcel.2022.01.018. Online ahead of print.
Poly(ADP-ribose) (PAR) is an RNA-like polymer that regulates a growing number of biological processes. Dysregulation of PAR is implicated in neurodegenerative diseases characterized by abnormal protein aggregation, including amyotrophic lateral sclerosis (ALS). PAR condensates with FUS, an RNA-binding protein linked to ALS, by an unknown mechanism. Here, we demonstrate that a surprisingly low concentration of PAR (1 nM) is sufficient to trigger the condensation of FUS near its physiological concentration (1 μM), which is three orders of magnitude lower than the concentration at which RNA induces condensation (1 μM). Unlike RNA, which associates with FUS in a stable manner, PAR interacts with FUS transiently, triggering the oligomerization of FUS into condensates. In addition, inhibition of a major PAR synthesis enzyme, PARP5a, decreases FUS condensation in cells. Despite their structural similarity, PAR and RNA co-condense with FUS, driven by disparate modes of interaction with FUS. Thus, we discover a mechanism by which PAR potently engenders the FUS condensation.
PMID:35182479 | DOI:10.1016/j.molcel.2022.01.018