6533b85efe1ef96bd12bf4dc

RESEARCH PRODUCT

The repair of oxidized purines in the DNA of human lymphocytes requires an activation involving NF-YA-mediated upregulation of OGG1.

subject

description

8-Oxoguanine DNA glycosylase (OGG1), which initiates the repair of DNA purine modifications such as 8-oxo-7,8-dihydroguanine (8-oxoG), is often regarded as a house keeping protein ubiquitously active in mammalian cells. We have analysed the repair rates of oxidized purines generated by photosensitization in peripheral human lymphocytes and observed that the cells were virtually unable to remove these lesions (less than 10% removal within 24h). However, stimulation of the lymphocytes with phytohemagglutinin (PHA) strongly accelerated the repair so that ∼30% of the lesions were repaired within 4h. Within 24h following PHA stimulation and preceding the induction of cell proliferation, Western blots revealed an approximately 4-fold up-regulation of OGG1. The levels of OGG1 mRNA were 4-fold increased already after 6h. Chromatin immunoprecipitation analysis indicated that the up-regulation of OGG1 was associated with increased binding of the transcription factor NF-YA to the promoter of the OGG1 gene. The binding of NF-YA and subsequent induction of OGG1 was inhibited in the presence of an inhibitor of Jun kinase, indicating an activation of the corresponding signalling pathway as the mechanism underlying this transcriptional up-regulation. Our results reveal a strict control of base excision repair in cells of the human immune system.