Cell cycle checkpoint rewiring after p53 loss blocks G1/S and G2/M progression through kinase control of a single RNA-binding protein  

Michael B. Yaffe1

1Koch Institute for Integrative Cancer Biology, Cambridge, USA

Abstract

In response to genotoxic stress and chemotherapy-induced DNA damage, cells activate p53 to arrest cell cycle progression, allowing time for repair. In irreparable damaged cells, p53 subsequently initiates programmed cell death. In tumour cells, however, the p53 pathway is dysfunctional, resulting in inappropriate cell survival, and re-wiring of cell cycle checkpoints by recruiting the p38MAPK/MK2 kinase pathway to control cell cycle machinery. 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 the G1/S and G2/M cell cycle checkpoints through induction of distinct target mRNAs. Unlike p53, which controls p21 gene transcription, MK2 and hnRNPA0 regulate the post-transcriptional stabilisation of p27Kip1 and Gadd45a mRNAs. This MK2/hnRNPA0 pathway drives cisplatin resistance in lung cancer, demonstrating the importance of post-transcriptional RNA control in the clinical response to anti-cancer chemotherapy. Furthermore, in the presence of a functional p53 response, this MK2/hnRNPA0 successor pathway is actively repressed through down-regulation of hnRNPA0 mRNA levels.