Regulation of stress granule maturation and dynamics by poly(ADP-ribose) interaction with PARP13

Abstract

Abstract Non-covalent interactions of poly(ADP-ribose) (PAR) facilitate condensate formation, yet the impact of these interactions on condensate properties remains unclear. Here, we demonstrate that PAR-mediated interactions through PARP13, specifically the PARP13.2 isoform, are essential for modulating the dynamics of stress granules—a class of cytoplasmic condensates that form upon stress, including types frequently observed in cancers. Single amino acid mutations in PARP13, which reduce its PAR-binding activity, lead to the formation of smaller yet more numerous stress granules than observed in the wild-type. This fragmented stress granule phenotype is also apparent in PARP13 variants with cancer-associated single-nucleotide polymorphisms (SNPs) that disrupt PAR binding. Notably, this fragmented phenotype is conserved across a variety of stresses that trigger stress granule formation via diverse pathways. Furthermore, this PAR-binding mutant diminishes condensate dynamics and impedes fusion. Overall, our study uncovers the important role of PAR-protein interactions in stress granule dynamics and maturation, mediated through PARP13.