ATM-Mediated Translocation of RanBPM Regulates DNA Damage Response by Stabilizing p21 in Non-Small Cell Lung Cancer Cells

Abstract

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-induced deaths around the world, and platinum-based chemotherapy remains a standard-of-care for most patients with advanced NSCLC. DNA damage response (DDR) induced by platinum or Etoposide activated a panel of cell cycle-regulatory proteins including p21 through p53 pathway. In this present study, we found that the level of p21 or RanBPM is lower in NSCLC than non-malignant tissues and has a highly positive correlation, which is negatively correlated with the survival of patients. We further revealed that RanBPM protein physically interacts with p21, RanBPM deubiquitinates p21 by recruiting a deubiquitinase USP11 to maintain protein stability of p21. Furthermore, RanBPM regulates DNA damage response (DDR) in a p21-dependent manner, and DNA damage promotes the translocation of RanBPM into the nucleus and regulates p21 protein stability through ATM-mediated pathways. We for the first time revealed a novel mechanism of p21 protein stability regulated by RanBPM, and the novel roles of RanBPM in the regulation of DDR.