RNA Binding Proteins Confer Resistance to DNA-Damaging Therapy

Defects in the DNA damage response network allow tumors to evade oncogene-induced cell senescence and can be preferentially targeted by cytotoxic drugs, which cause DNA damage in tumor cells and result in cell-cycle arrest and/or death. However, some tumor types are resistant to chemotherapy, and it has recently been shown that the survival of TP53-mutant tumors in response to cytotoxic drugs depends on the MAPK-activated protein kinase 2 (MK2) pathway, which post-transcriptionally controls the G2/M cell-cycle checkpoint by phosphorylation of the RNA-binding protein heterogeneous nuclear ribonucleoprotein A0 (hnRNPA0) and stabilization of growth arrest and DNA damage–inducible α (GADD45A) mRNA. Cannell and colleagues investigated the role of MK2—hnRNPA0-mediated regulation of cell-cycle checkpoints in the chemotherapeutic response of TP53-mutant non–small cell lung cancer (NSCLC), which is frequently resistant to cytotoxic therapy. Expression profiling of G1/S regulators revealed that depletion of hnRNPA0, which also induces loss of the G1/S checkpoint, resulted in decreased cyclin-dependent kinase 1B (CDKN1B, also known as p27^Kip1) expression. Consistent with this finding, hnRNPA0 directly bound to the 3′-UTR of the p27^Kip1 transcript, resulting in stabilization of p27^Kip1 mRNA. Knockdown experiments identified p27^Kip1 as the primary hnRNPA0 target mRNA controlling the DNA damage–induced G1/S checkpoint in TP53-null cells and showed that DNA damage–induced MK2 phosphorylation of hnRNPA0 was necessary for its binding to p27^Kip1 and GADD45A and cytoplasmic accumulation of hnRNPA0. Depletion of hnRNPA0 sensitized TP53-deficient NSCLC cells to cytotoxic chemotherapy both in vitro and in vivo. Mechanistically, hnRNPA0 promoted chemoresistance of TP53-deficient cells by coordinately stabilizing p27^Kip1 and GADD45A mRNAs, which were inversely correlated with survival of patients with NSCLC treated with cytotoxic chemotherapy. This MK2–hnRNPA0 pathway was mutually exclusive with the p53–p21 pathway, which induced hnRNPA0 mRNA destabilization. These results show that the MK2—hnRNPA0 pathway promotes resistance to DNA-damaging chemotherapy by reinstating cell-cycle checkpoint control in the absence of p53.

Cannell IG, Merrick KA, Morandell S, Zhu CQ, Braun CJ, Grant RA, et al. A pleiotropic RNA-binding protein controls distinct cell cycle checkpoints to drive resistance of p53-defective tumors to chemotherapy. Cancer Cell 2015 Oct 22 [Epub ahead of print].