Fusion Protein of Retinoic Acid Receptor ! with Promyelocytic Leukemia Protein or Promyelocytic Leukemia Zinc Finger Protein Recruits N-CoR-TBLR1 Corepressor Complex to Repress Transcription in Vivo*

Fusion proteins of retinoic acid receptor ! (RAR!) with promyelocytic leukemia protein (PML-RAR!) or with promyelocytic leukemia zinc finger protein (PLZFRAR!) are associated with and likely responsible for the development of acute promyelocytic leukemia. These oncoproteins retain the ability to bind DNA and retinoic acid through the RAR! moiety. This enables them to repress RAR! target genes in the absence of retinoic acid, but the underlying mechanisms remain to be investigated. Here we use the frog oocyte system to study transcriptional regulation by PML-RAR! and PLZFRAR! in the context of chromatin. We first show that the endogenous corepressor N-CoR forms a complex with TBLR1 (transducin beta-like protein 1-related protein) and that both N-CoR and TBLR1 can interact with unliganded PML-RAR! and PLZF-RAR! in vivo. Using chromatin immunoprecipitation, we demonstrate that both oncoproteins recruit TBLR1, as well as N-CoR, to its target promoter, leading to histone deacetylation and transcriptional repression. Furthermore, expression of a dominant negative N-CoR that contains the TBLR1-interacting domain blocks transcription repression by unliganded PML-RAR! and PLZF-RAR!. Thus, our studies provide in vivo evidence for targeted recruitment of NCoR-TBLR1 complexes by PML-RAR! and PLZF-RAR! in transcriptional repression in the context of chromatin.