p53 mRNA availability during the cellular stress response is controlled by Cdc73 sequestration to stress granules

Abstract

ABSTRACTCells trigger the assembly of stress granules (SGs) under various stress conditions. Among the many proteins recruited to SGs are RNA-binding proteins (RBPs) and regulators of transcription. Here, we report the translocation of hCdc73, a component of the PAF1 transcription complex, to cytosolic SGs in response to sodium arsenite, MG132, thapsigargin (TG) or heat treatment. The hCdc73 protein possesses a long intrinsically disordered region (IDR) from amino acids 256-416, the presence of which is required and essential for the translocation of hCdc73 to cytosolic SGs. The purified hCdc73 IDR formed droplets in vitro, and the light-activated assembly of hCdc73 IDR-Cry2 was also verified. Alone, the hCdc73 IDR, however, was not sufficient for the translocation of hCdc73 to SGs, as physical interactions with the scaffold proteins of SGs, such as FMR1, were needed. Selective sequestration of cytosolic hCdc73 into SGs coincided with the dissociation of p53 mRNA from the hCdc73/Ski8/eEF1Bγ complex, resulting in a transient rise in p53 mRNA at the posttranscriptional level. In conclusion, we propose that in addition to the storage of nontranslating mRNAs, SGs also function to control the availability of mRNAs for stress response genes by restraining their negative regulators within SGs.