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Pus3p- and Pus1p-Dependent Pseudouridylation of Steroid Receptor RNA Activator Controls a Functional Switch that Regulates Nuclear Receptor Signaling

Departments of Otolaryngology and Biochemistry (X.Z., L.S., R.A.S.), Cancer Research Center, Boston University School of Medicine, Boston, Massachusetts 02118; Department of Pathology and Microbiology (J.R.P.), University of South Carolina School of Medicine, Columbia, South Carolina 29208; Department of Medicine (S.K.G.), Cancer Research Center, Boston University School of Medicine, Boston, Massachusetts 02118; and Department of Pediatrics and Medical Genetics Institute (N.F.-G.), Cedars-Sinai Medical Center, University of California, Los Angeles, School of Medicine, Los Angeles, California 90048

Address all correspondence and requests for reprints to: Remco A. Spanjaard, Ph.D., Cancer Research Center, Boston University School of Medicine, 715 Albany Street R903, Boston, Massachusetts 02118. E-mail: rspan{at}bu.edu.

It was previously shown that mouse Pus1p (mPus1p), a pseudouridine synthase (PUS) known to modify certain transfer RNAs (tRNAs), can also bind with nuclear receptors (NRs) and function as a coactivator through pseudouridylation and likely activation of an RNA coactivator called steroid receptor RNA activator (SRA). Use of cell extract devoid of human Pus1p activity derived from patients with mitochondrial myopathy and sideroblastic anemia, however, still showed SRA-modifying activity suggesting that other PUS(s) can also target this coactivator. Here, we show that related mPus3p, which has a different tRNA specificity than mPus1p, also serves as a NR coactivator. However, in contrast to mPus1p, it does not stimulate sex steroid receptor activity, which is likely due to lack of binding to this class of NRs. As expected from their tRNA activities, in vitro pseudouridylation assays show that mPus3p and mPus1p modify different positions in SRA, although some may be commonly targeted. Interestingly, the order in which these enzymes modify SRA determines the total number of pseudouridines. mPus3p and SRA are mainly cytoplasmic; however, mPus3p and SRA are also localized in distinct nuclear subcompartments. Finally, we identified an in vivo modified position in SRA, U206, which is likely a common target for both mPus1p and mPus3p. When U206 is mutated to A, SRA becomes hyperpseudouridylated in vitro, and it acquires dominant-negative activity in vivo. Thus, Pus1p- and Pus3p-dependent pseudouridylation of SRA is a highly complex posttranscriptional mechanism that controls a coactivator-corepressor switch in SRA with major consequences for NR signaling.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRβ  |  RARβ  |  RARγ  |  VDR  |  ERα  |  GR  |  PR  |  AR

Coregulators:   PUS1  |  SRA

Ligands:   17β-Estradiol  |  Dihydrotestosterone

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