Tia1 dependent regulation of mRNA subcellular location and translation controls p53 expression in B cells

• DOI: 10.1038/s41467-017-00454-2
• Publication Date: 2017-09-11T10:17:21Z
• Authors: Manuel D. Díaz-Muñoz; Vladimir Yu. Kiselev; Nicolas Le Novère; Tomaz Curk; Jernej Ule; Martin Turner
• Keywords: V(D)J RECOMBINATION; 0301 basic medicine; Science; Ataxia Telangiectasia Mutated Proteins; Lymphocyte Activation; Article; 03 medical and health sciences; GERMINAL-CENTER; Animals; Humans; ATAXIA-TELANGIECTASIA; DEFICIENT LYMPHOCYTES; RNA, Messenger; 3' Untranslated Regions; MAMMALIAN STRESS GRANULES; Etoposide; B-Lymphocytes; Science & Technology; Q; GENOTOXIC STRESS; T-Cell Intracellular Antigen-1; Multidisciplinary Sciences; MHC CLASS-I; Mice, Inbred C57BL; HEK293 Cells; DNA-DAMAGE; Gene Expression Regulation; Protein Biosynthesis; Science & Technology - Other Topics; GENOMIC STABILITY; Tumor Suppressor Protein p53; CLASS SWITCH RECOMBINATION; DNA Damage

AbstractPost-transcriptional regulation of cellular mRNA is essential for protein synthesis. Here we describe the importance of mRNA translational repression and mRNA subcellular location for protein expression during B lymphocyte activation and the DNA damage response. Cytoplasmic RNA granules are formed upon cell activation with mitogens, including stress granules that contain the RNA binding protein Tia1. Tia1 binds to a subset of transcripts involved in cell stress, including p53 mRNA, and controls translational silencing and RNA granule localization. DNA damage promotes mRNA relocation and translation in part due to dissociation of Tia1 from its mRNA targets. Upon DNA damage, p53 mRNA is released from stress granules and associates with polyribosomes to increase protein synthesis in a CAP-independent manner. Global analysis of cellular mRNA abundance and translation indicates that this is an extended ATM-dependent mechanism to increase protein expression of key modulators of the DNA damage response.