Posttranscriptional gene regulation by RNA-binding proteins during oxidative stress: implications for cellular senescence

Abstract

To respond adequately to oxidative stress, mammalian cells elicit rapid and tightly controlled changes in gene expression patterns. Besides alterations in the subsets of transcribed genes, two posttranscriptional processes prominently influence the oxidant-triggered gene expression programs: mRNA turnover and translation. Here, we review recent progress in our knowledge of the turnover and translation regulatory (TTR) mRNA-binding proteins (RBPs) that influence gene expression in response to oxidative damage. Specifically, we identify oxidant damage-regulated mRNAs that are targets of TTR-RBPs, we review the oxidant-triggered signaling pathways that govern TTR-RBP function, and we examine emerging evidence that TTR-RBP activity is altered with senescence and aging. Given the potent influence of TTR-RBPs upon oxidant-regulated gene expression profiles, we propose that the senescence-associated changes in TTR-RBPs directly contribute to the impaired responses to oxidant damage that characterize cellular senescence and advancing age.

Figure 1. Oxidative stress-activated pathways influencing TTR-RBP activity.

Green boxes: effector kinases in signaling cascades activated or repressed by oxidative stress. Yellow ovals: TTR-RBPs that are downstream of the effector kinases, either as direct phosphorylation substrates (solid arrow) or as indirect effectors (discontinuous arrow). ‘?’, evidence of phosphorylation available only from in vitro studies. Phosphorylated residues (threonines and serines) are indicated below the oval and phosphorylation linked to association with 14–3-3 (orange) is shown. Blue squares: changes in subcellular localization, association with cellular compartments (SGs, exosome) or binding to target mRNAs following modification of TTR-RBPs by the signaling cascades. Black boxes: consequences of TTR-RBP/RNP modifications upon the expression and translation of the mRNA.