Human NRH:
quinone oxidoreductase 2 (
NQO2) gene-containing 29-bp deletion/insertion polymorphic promoters were found to be associated with susceptibility to
Parkinson's disease. Here, we demonstrate that the
NQO2 gene is differentially expressed by the polymorphic promoters in human fibroblasts and Hep-G2 cells transfected with
NQO2 gene reporter constructs. Promoter containing the 29-bp insertion polymorphism demonstrated significantly lower
NQO2 gene expression. Deletion mutagenesis and
DNase I footprinting analysis of the promoter without the 29-bp insertion identified three protected regions (region A, B, and C). Band- and supershift and transfection assays showed binding of
transcription factor Sp1 to regions A and B, which regulated expression of the
NQO2 gene. Similar studies of the
NQO2 gene promoter with the 29-bp insertion polymorphism showed that regions A and C were identical and contributed similarly as in the promoter without the 29-bp insertion to
NQO2 gene expression. However, region B was found to be inserted with 29-bp
DNA element and bound to both Sp1 and Sp3. Binding of Sp3 led to repression of
NQO2 gene transcription by the promoter containing the 29-bp insertion polymorphism. These studies also suggest that alterations in
NQO2 activity might be an important factor in susceptibility to
Parkinson's disease.