Authors:
Ian G. Cannell, Karl A. Merrick, Sandra Morandell, Chang-Qi Zhu, Christian J. Braun, Robert A. Grant, Eleanor R. Cameron, Ming-Sound Tsao, Michael T. Hemann, & Michael B. Yaffe
Summary:
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 p21cip1 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 p27Kip1 and Gadd45α mRNAs. This pathway drives cisplatin resistance in lung cancer, demonstrating the importance of post-transcriptional RNA control to chemotherapy response.
Source:
Cancer Cell; (10/22/15)