Abstract
URI (unconventional prefoldin RPB5 interactor protein) is an unconventional prefoldin, RNA polymerase II interactor that functions as a transcriptional repressor and is part of a larger nuclear protein complex. The components of this complex and the mechanism of transcriptional repression have not been characterized. Here we show that KAP1 (KRAB-associated protein 1) and the protein phosphatase PP2A interact with URI. Mechanistically, we show that KAP1 phosphorylation is decreased following recruitment of PP2A by URI. We functionally characterize the novel URI-KAP1-PP2A complex, demonstrating a role of URI in retrotransposon repression, a key function previously demonstrated for the KAP1-SETDB1 complex. Microarray analysis of annotated transposons revealed a selective increase in the transcription of LINE-1 and L1PA2 retroelements upon knockdown of URI. These data unveil a new nuclear function of URI and identify a novel post-transcriptional regulation of KAP1 protein that may have important implications in reactivation of transposable elements in prostate cancer cells.
Highlights
From the ‡Institute of Systems Genetics and the Departments of §§Biochemistry and Molecular Pharmacology, ¶Urology, and
URI/C19orf2 has been characterized as a transcriptional repressor, but little is known about the mechanisms by which
URI Binds Active PP2A Phosphatase—Our experiments suggest that URI binds and regulates the phosphorylation of KAP1
Summary
In Saccharomyces cerevisiae, URI binds the phosphorylated C-terminal domain (CTD) of RNA polymerase II and affects the recruitment of the chromatin remodeling complex RSC [10]. KAP1 functions as a scaffold for the recruitment of a repression complex that includes histone deacetylases [13], HP1 (heterochromatin protein 1) [14], and the histone methyltransferase SETDB1 [15]. The abbreviations used are: CTD, C-terminal domain; LINE-1, long interspersed element 1; PP, protein phosphatase; IP, immunoprecipitated or immunoprecipitation; Pol, polymerase; OA, okadaic acid; TE, transposable element; MAD, median absolute deviation; qPCR, quantitative PCR; aa, amino acid(s); siCtrl, siRNA control. Serine and threonine phosphatases PP1␣ and PP1 were previously shown to dephosphorylate KAP1 Ser824, enabling repression of target genes [32]
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