Increased risk of lung cancer associated with a functionally impaired polymorphic variant of the human DNA glycosylase NEIL2

► R257L and R103Q, the two variants of NEIL2, predominantly present in patients with squamous cell lung carcinoma, are linked and inherited together in the population. ► R257L shows only a modest decrease (∼1.5-fold) in DNA glycosylase activity; however, the total BER activity is significantly decreased (∼5-fold) compared to the wild type enzyme. ► Decreased interaction of the R257L variant with downstream proteins in the BER pathway, particularly with DNA polymerase β, contributes to reduced repair. ► R257L-expressing cells accumulate significant amounts of endogenous DNA damage. ► Depletion of NEIL2 in Chinese hamster lung V79 cells induced higher spontaneous mutation frequency, indicating the role of NEIL2 in repairing endogenous, oxidative genome damage.