Oxidative stress has been implicated as one of the primary mechanisms inducing DNA damage and believed to mediate aging and progression of numerous age-related diseases, including cancer. JWA, a gene previously described to mediate differentiation of leukemic cells, is also involved in cellular responses to environmental exposures linked to heat shock and chemical-mediated oxidative stresses. However, the precise pathways and mechanisms underlying these phenomena remain to be resolved. Our studies demonstrated that H(2)O(2) is the primary oxidative product responsible for benzo[a]pyrene (B[a]P)-induced JWA expression, and knockdown of JWA elevates H(2)O(2) (100 microM)- and B[a]P (100 microM)-induced DNA damage. In oxidative stress cell culture models, JWA was upregulated. JWA expression regulated a parallel rise in the base excision repair protein XRCC1 but a reduction in PARP1 in response to H(2)O(2)-induced DNA damage. Furthermore, we found that both H(2)O(2) and B[a]P exposure activated nuclear transcription factor I (NFI) in NIH-3T3 cells, which specifically bound to the CCAAT element in the JWA proximal promoter (-58/-28 bp) and thereby induced JWA expression. Consistently siRNA mediated a knockdown of NFI, which prevented JWA induction. These findings indicate that JWA may serve as a novel environmental stress sensor to protect cells against reactive oxygen species-associated DNA damage.