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

• Main Authors: Grant, Robert A (Author), Tsao, Ming-Sound (Author), Cannell, Ian Gordon (Contributor), Merrick, Karl Andrew (Contributor), Morandell, Sandra M. (Contributor), Grant, Robert A (Contributor), Cameron, Eleanor Ruth (Contributor), Hemann, Michael (Contributor), Yaffe, Michael B (Contributor), Braun, Christian Joerg (Author)
• Other Authors: Massachusetts Institute of Technology. Department of Biological Engineering (Contributor), Massachusetts Institute of Technology. Department of Biology (Contributor), Koch Institute for Integrative Cancer Research at MIT (Contributor), Braun, Christian Jorg (Contributor)
• Format: Article
• Language: English
• Published: Elsevier, 2016-12-01T19:41:32Z.
• Subjects: Article
• Online Access: Get fulltext

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.
Austrian Science Fund (Grant J 2900-B21)
German Cancer Aid (Mildred-Scheel Fellowship)
Damon Runyon Cancer Research Foundation (Grant DRG 2127-12)
National Institutes of Health (U.S.) (Grants ES015339, GM60594, GM59281 and CA112967)
Anna Fuller Fund
David H. Koch Institute for Integrative Cancer Research at MIT (Core Grant P30-CA14051)
Massachusetts Institute of Technology. Center for Environmental Health Sciences (Core Grant ES-002109)