Journal
CANCER CELL
Volume 28, Issue 5, Pages 623-637Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2015.09.009
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Funding
- Austrian Science Fund (FWF) [J 2900-B21]
- German Cancer Foundation
- Damon Runyon Cancer Research Foundation [DRG 2127-12]
- Canadian Cancer Society Research Institute [020527]
- NIH [ES015339, GM60594, GM59281, CA112967]
- Koch Institute and Center for Environmental Health Sciences Core [P30-CA14051, ES-002109]
- Anna Fuller Fund
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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(cip1) and Gadd45 alpha. 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(Kip1) and Gadd45 alpha mRNAs. This pathway drives cisplatin resistance in lung cancer, demonstrating the importance of post-transcriptional RNA control to chemotherapy response.
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