Regulation of nuclear receptor transcriptional activity by a novel DEAD box RNA helicase (DP97)

Abstract

We have identified a novel DEAD box RNA helicase (97 kDa, DP97) from a breast cancer cDNA library that interacts in a hormone-dependent manner with nuclear receptors and represses their transcriptional activity. DP97 has RNA-dependent ATPase activity, and mapping studies localize the interacting regions of DP97 and nuclear receptors to the C-terminal region of DP97 and the hormone binding/activation function-2 region of estrogen receptors (ER), as well as several other nuclear receptors. Repression by DP97 maps to a small region (amino acids 589-631) that has homology to a repression domain in the corepressor protein NCoR2/SMRTe. This region of DP97 is necessary and sufficient for its intrinsic repression activity. The N-terminal helicase region of DP97 is, however, dispensable for its transcriptional repressor activity. The knockdown of endogenous cellular DP97 by antisense DP97 or RNA interference (siRNA for DP97) results in significant enhancement of the expression of estradiol-ER-stimulated genes and attenuation of the repression of genes inhibited by the estradiol-ER. This implies that endogenous DP97 normally dampens stimulation and intensifies repression of estra-diol-ER-regulated genes. Our findings add to the growing evidence that RNA helicases can associate with nuclear receptors and function as coregulators to modulate receptor transcriptional activity.