Poly(ADP-ribose) Polymerase 1 Is a Key Regulator of Estrogen Receptor α-dependent Gene Transcription

Abstract

Activation of nuclear receptor estrogen receptor α (ERα) exerts cardiovascular protective effects by modulating the expression of ERα target genes. However, the underlying mechanism remains unclear. PARP1 is a ubiquitous multifunctional nuclear enzyme. In this study, we examined the interplay between PARP1 and ERα, and identified PARP1 as an important regulator of ERα-dependent transcription. We showed that PARP1 could directly bind to ERα, and ERα could be poly(ADP-ribosyl)ated by PARP1. Poly(ADP-ribosyl)ation increased ERα binding to estrogen response element (ERE) present in the promoter of target genes and promoted ERα-mediated gene transcription. Estradiol, the ligand of ERα, increased PARP enzymatic activity and enhanced poly(ADP-ribosyl)ation of ERα. Upon treatment with estradiol, ERα binding to ERE- and ERα-dependent gene expression was dramatically increased in cultured vascular smooth muscle cells (VSMCs). Inhibition of PARP1 by PARP inhibitor or PARP1 siRNA decreased ERα binding to ERE and prevented ERα-dependent gene transcription in VSMCs. Further studies revealed that PARP1 served as an indispensible component for the formation of the ERα-ERE complex by directly interacting with ERα. Thus, our results identify PARP1 as a key regulator of ERα in controlling ERα transactivation.