Disordered Protein Tail Is Wagging Poly(ADP-ribosyl)ation.

Intrinsically disordered regions (IDRs) are present in nearly all proteins, often accounting for more than 40% of their amino acid sequence. Unlike structured domains, IDRs lack sequence or structural conservation across species while maintaining conserved biological functions. Here, we discovered that the previously uncharacterized disordered tail region of Poly(ADP-ribose) glycohydrolase (PARG) controls its localization and activity. Despite its structural divergence, this domain supports conserved regulatory functions across species. Deletion of the disordered tail results in cytoplasmic mislocalization, aberrant accumulation in the nucleolus, impaired chromatin association, and reduced enzymatic activity. Mass spectrometry analysis reveals that this disordered region mediates interactions with nuclear transport factors, post-translational modification enzymes, and chromatin-associated complexes. Together, these results demonstrate that the disordered tail region of PARG acts as a regulatory hub that integrates multiple layers of control to ensure proper subcellular localization and chromatin function.