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Background  Non‐small cell lung cancer ( NSCLC ) harboring kinase‐domain mutations in epidermal growth factor receptors ( EGFR ) has been observed to be sensitive to ionizing radiation ( IR ). We explore  R ad51‐dependent homologous recombination ( HR )  DNA  repair in regulating radiosensitivity in two  NSCLC  cell lines with different  EGFR  mutation status.    Methods   NSCLC  cell lines, wild‐type  EGFR A 549 and mutant  EGFR H 820 with an in‐frame deletion in exon 19 of  EGFR  (Δ E 746– E 750), were cultured. Radiosensitivity was estimated by colony forming assay.  R ad51 expression was evaluated by quantitative real time‐polymerase chain reaction and  W estern‐blot. Lentiviral small hairpin ribonucleic acid‐ R ad51 and Δ E 746– E 750 deletion mutant  EGFR  were constructed and transfected into cells. Flowcytometry assay was used to analyze  DNA  double strand breaks, cell cycle alterations, and apoptosis.    Results   A 549 had a higher survival factor ( SF )2 (0.66 vs. 0.44) and lower α/β value (4.07 vs. 9.01). Compared with the  A 549 cell, the  H 820 cell exhibited defective arrest in the  S ‐phase, a higher rate of  G2/M  accumulation, early apoptosis, and residual γ‐ H2AX . Downregulated Rad51 expression decreased  SF 2 (0.42 vs. 0.31) and increased the α/β ratio (7.51 vs. 10.5),  G2/M  accumulation, early apoptosis, and γ‐ H2AX  in two cell lines.  H 820 had a low  IR ‐induced  R ad51 expression and nuclear translocation. Exogenous expression of the Δ E 746– E 750 deletion mutant  EGFR  caused the  A 549 cell to become more radiosensitive.    Conclusions  An  EGFR  mutated  NSCLC  cell line is sensitive to  IR  ,  which is correlated with reduced  IR ‐induced  R ad51 expression and nuclear translocation. The signaling pathway of  EGFR  maintaining  R ad51 protein levels maybe a novel lung cancer therapeutic target to overcome radioresistance.

R ad51 in regulating the radiosensitivity of non‐small cell lung cancer with different epidermal growth factor receptor mutation status