Interaction of estrogen receptor alpha with 3-methyladenine DNA glycosylase modulates transcription and DNA repair.

Estrogen receptor alpha (ERalpha) interacts with basal transcription factors, coregulatory proteins, and chromatin modifiers to initiate transcription of the target genes. We have identified a novel interaction between ERalpha and the DNA repair protein 3-methyladenine DNA glycosylase (MPG) thereby providing a functional link between gene expression and DNA repair. Interestingly, the ERalpha-MPG interaction was enhanced by the presence of estrogen response element (ERE)-containing DNA. In vitro pull-down assays indicated that the interaction of ERalpha with MPG was direct and occurred through the DNA- and ligand-binding domains and the hinge region of the receptor. More importantly, endogenously expressed ERalpha and MPG from MCF-7 cells coimmunoprecipitated with ERalpha- and MPG-specific antibodies. The ERalpha-MPG interaction had functional consequences on the activities of both proteins. ERalpha increased MPG acetylation, stabilized the binding of MPG with hypoxanthine-containing oligos, and enhanced MPG-catalyzed removal of hypoxanthine from DNA. In turn, MPG dramatically stabilized the interaction of ERalpha with ERE-containing oligos, decreased p300-mediated acetylation of the receptor, and reduced transcription of simple and complex ERE-containing reporter plasmids in a dose-dependent manner. Our studies suggest that recruitment of MPG to ERE-containing genes influences transcription and plays a role in maintaining integrity of the genome by recruiting DNA repair proteins to actively transcribing DNA.