We show that reexpression of NPRL2 in NPRL2-negative and cisplatin-resistant cells significantly activates those key components, including ATM, Chk, and H2AX, and resensitizes lung cancer cells to cisplatin treatment in vitro and in vivo, leading to cell cycle arrest in the G2/M phase and induction of apoptosis. Here, H2AX is linked to lung cancer.