A Pleiotropic RNA-Binding Protein Controls Distinct Cell Cycle Checkpoints to Drive Resistance of p53-Defective Tumors to Chemotherapy

Abstract

In normal cells p53 is activated by DNA damage checkpoint kinases to simultaneously control the G1/S and G2/M cell cycle checkpoints through transcriptional induction of p21[superscript cip1] and Gadd45α. In p53 mutant tumors, cell cycle checkpoints are rewired, leading to dependency on the p38/MK2 pathway to survive DNA-damaging chemotherapy. Here we show that the RNA binding protein hnRNPA0 is the “successor” to p53 for checkpoint control. Like p53, hnRNPA0 is activated by a checkpoint kinase (MK2) and simultaneously controls both cell cycle checkpoints through distinct target mRNAs, but unlike p53 this is through the post-transcriptional stabilization of p27[superscript Kip1] and Gadd45α mRNAs. This pathway drives cisplatin resistance in lung cancer demonstrating the importance of post-transcriptional RNA control to chemotherapy response.