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

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