Translocation of cytosolic human Cdc73 to stress granules plays a role in arsenic stress-induced stabilization of p53 mRNA

Abstract

ABSTRACT Cells trigger the assembly of stress granules (SGs) under various stress conditions. Among the many proteins recruited to SGs are RNA-binding proteins and transcription regulators. Here, we report the translocation of human (h)Cdc73, a component of the PAF1 transcription complex, to cytosolic SGs in response to arsenic stress. The hCdc73 protein possesses a long intrinsically disordered region (IDR) from amino acids 256–416, the presence of which is required for the translocation of hCdc73 to cytosolic SGs. The purified hCdc73 IDR formed droplets in vitro, and the light-activated assembly of hCdc73-IDR–mCherry–CRY2 was verified. For translocation of hCdc73 to SGs, physical interactions with SG carrier proteins, such as FMR1, are also needed. Previously, we reported that the cytosolic hCdc73–eEF1Bγ complex controls the stability of p53 mRNA. Under arsenic stress, selective sequestration of cytosolic hCdc73, but not eEF1Bγ (EEF1G) or p53 (TP53) mRNA, was detected. As a result, a transient increase in p53 mRNA at the post-transcriptional level was observed. In conclusion, we propose that the availability of mRNAs for stress-responsive genes can be controlled by restraining their negative regulators within SGs.