Tob2 phosphorylation regulates global mRNA turnover to reshape transcriptome and impact cell proliferation.

In this study, we found that c-Jun N-terminal kinase (JNK) increases phosphorylation of Tob2 at many Ser/Thr sites in the intrinsically disordered region (IDR) that contains two separate PABP-interacting PAM2 motifs. JNK-induced phosphorylation or phosphomimetic mutations at these sites weaken the Tob2-PABP interaction. In contrast, JNK-independent phosphorylation of Tob2 at serine 254 (S254) greatly enhances Tob2 interaction with PABP and its ability to promote deadenylation. We discovered that both PAM2 motifs are required for Tob2 to display these features. Combining mass spectrometry analysis, poly(A) size-distribution profiling, transcriptome-wide mRNA turnover analyses, and cell proliferation assays, we found that the phosphomimetic mutation at S254 (S254D) enhances Tob2's association with PABP, leading to accelerated deadenylation and decay of mRNAs globally. Moreover, the Tob2-S254D mutant accelerates the decay of many transcripts coding for cell-cycle related proteins and enhances anti-proliferation function. Our findings reveal a novel mechanism by which Ccr4-Not complex is recruited by Tob2 to the mRNA 3' poly(A)-PABP complex in a phosphorylation dependent manner to promote rapid deadenylation and decay across the transcriptome, eliciting transcriptome reprogramming and suppressed cell proliferation.
PMID: 32404348 [PubMed - as supplied by publisher]

Source: RNA - May 12, 2020 Category: Genetics & Stem Cells Authors: Chen CA, Strouz K, Huang KL, Shyu AB Tags: RNA Source Type: research