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Purpose: Platinum-based chemotherapy remains a standard-of-care for most patients with advanced non-small cell lung cancer (NSCLC). DNA damage response (DDR) induced by platinum or Etoposide activated a panel of cell cycle-regulatory proteins including p21 through p53 pathway. Previous studies have reported that RanBPM has been involved in various cellular processes such as DDR by interacting with multiple proteins. However, the underlying mechanism remains unclear. Methods: NSCLC tissue microarrays were used for assessing the expression of RanBPM by immunohistochemical staining. The roles of RanBPM in the DDR of NSCLC progression was examined in in vitro cell lines and in vivo animal models. The regulation of RanBPM on protein stability and ubiquitination levels were investigated by immunoblots and in vivo ubiquitylation assay. Results: The level of p21 or RanBPM is lower in NSCLC than non-malignant tissues and has a highly positive correlation. Mechanistically, RanBPM protein physically interacts with p21, and RanBPM deubiquitinates p21 by recruiting a deubiquitinase USP11 to maintain protein stability of p21. RanBPM silencing significantly decreased p21 protein level. Conversely, RanBPM overexpression led to the accumulation of endogenous p21 protein regardless of p53 status. Functionally, RanBPM regulates DDR in a p21-dependent manner. Furthermore, DNA damage significantly promoted the nuclear translocation of RanBPM protein through ATM signaling pathways. Conclusion: RanBPM is a novel regulator of P21 protein stability, and plays a critical role in the regulation of DDR. [ABSTRACT FROM AUTHOR]