Ubiquitin and Proteasomes in Transcription

Geng, Fuqiang; Wenzel, Sabine; Tansey, William P.

doi:10.1146/annurev-biochem-052110-120012

Cited by 261 publications

(288 citation statements)

References 158 publications

(175 reference statements)

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“…Notably, in rpn2 cells, the fraction of the slower-mobility species decreased to B20%, suggesting that fully assembled proteasomes, rather than constituent subcomplexes, associate with these cellular components. Recent studies suggested that cytoplasmic proteasomes interact directly with actin fibres 35 , and that nuclear proteasomes associate with chromatin during the transcription process 36 . To test these ideas, we exposed cells to drugs targeting these features of the cell.…”

Section: Resultsmentioning

confidence: 99%

Quantitative live-cell imaging reveals spatio-temporal dynamics and cytoplasmic assembly of the 26S proteasome

et al. 2014

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The 26S proteasome is a 2.5-MDa multisubunit protease complex that degrades polyubiquitylated proteins. Although its functions and structure have been extensively characterized, little is known about its dynamics in living cells. Here, we investigate the absolute concentration, spatio-temporal dynamics and complex formation of the proteasome in living cells using fluorescence correlation spectroscopy. We find that the 26S proteasome complex is highly mobile, and that almost all proteasome subunits throughout the cell are stably incorporated into 26S proteasomes. The interaction between 19S and 20S particles is stable even in an importin-a mutant, suggesting that the 26S proteasome is assembled in the cytoplasm. Furthermore, a genetically stabilized 26S proteasome mutant is able to enter the nucleus. These results suggest that the 26S proteasome completes its assembly process in the cytoplasm and translocates into the nucleus through the nuclear pore complex as a holoenzyme.

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Section: Resultsmentioning

confidence: 99%

Quantitative live-cell imaging reveals spatio-temporal dynamics and cytoplasmic assembly of the 26S proteasome

et al. 2014

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“…In the cell, regulators of transcription usually undergo rapid turnover through the UPS [58,59]. Indeed, proteins involved in transcription initiation were stabilized by BTZ treatment and over-represented in PPI network analysis of the ProTA-BTZ hits ( Figure 4A).…”

Section: Cross Analysis Of Btz-induced Global Changes In Transcriptommentioning

confidence: 99%

Profiling human protein degradome delineates cellular responses to proteasomal inhibition and reveals a feedback mechanism in regulating proteasome homeostasis

Tao

Yang

et al. 2014

Cell Res

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Global change in protein turnover (protein degradome) constitutes a central part of cellular responses to intrinsic or extrinsic stimuli. However, profiling protein degradome remains technically challenging. Recently, inhibition of the proteasome, e.g., by using bortezomib (BTZ), has emerged as a major chemotherapeutic strategy for treating multiple myeloma and other human malignancies, but systematic understanding of the mechanisms for BTZ drug action and tumor drug resistance is yet to be achieved. Here we developed and applied a dual-fluorescence-based Protein Turnover Assay (ProTA) to quantitatively profile global changes in human protein degradome upon BTZ-induced proteasomal inhibition. ProTA and subsequent network analyses delineate potential molecular basis for BTZ action and tumor drug resistance in BTZ chemotherapy. Finally, combined use of BTZ with drugs targeting the ProTA-identified key genes or pathways in BTZ action reduced BTZ resistance in multiple myeloma cells. Remarkably, BTZ stabilizes proteasome subunit PSMC1 and proteasome assembly factor PSMD10, suggesting a previously under-appreciated mechanism for regulating proteasome homeostasis. Therefore, ProTA is a novel tool for profiling human protein degradome to elucidate potential mechanisms of drug action and resistance, which might facilitate therapeutic development targeting proteostasis to treat human disorders.

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“…The contribution of the proteasome to transcription regulation has been extensively documented (reviewed in refs [40][41][42]. In particular, proteasome-mediated degradation has been shown to directly affect transcription by coupling transcription factor turnover to activation.…”

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confidence: 99%

dDsk2 regulates H2Bub1 and RNA polymerase II pausing at dHP1c complex target genes

et al. 2015

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dDsk2 is a conserved extraproteasomal ubiquitin receptor that targets ubiquitylated proteins for degradation. Here we report that dDsk2 plays a nonproteolytic function in transcription regulation. dDsk2 interacts with the dHP1c complex, localizes at promoters of developmental genes and is required for transcription. Through the ubiquitin-binding domain, dDsk2 interacts with H2Bub1, a modification that occurs at dHP1c complex-binding sites. H2Bub1 is not required for binding of the complex; however, dDsk2 depletion strongly reduces H2Bub1. Co-depletion of the H2Bub1 deubiquitylase dUbp8/Nonstop suppresses this reduction and rescues expression of target genes. RNA polymerase II is strongly paused at promoters of dHP1c complex target genes and dDsk2 depletion disrupts pausing. Altogether, these results suggest that dDsk2 prevents dUbp8/Nonstop-dependent H2Bub1 deubiquitylation at promoters of dHP1c complex target genes and regulates RNA polymerase II pausing. These results expand the catalogue of nonproteolytic functions of ubiquitin receptors to the epigenetic regulation of chromatin modifications.

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Ubiquitin and Proteasomes in Transcription

Cited by 261 publications

References 158 publications

Quantitative live-cell imaging reveals spatio-temporal dynamics and cytoplasmic assembly of the 26S proteasome

Quantitative live-cell imaging reveals spatio-temporal dynamics and cytoplasmic assembly of the 26S proteasome

Profiling human protein degradome delineates cellular responses to proteasomal inhibition and reveals a feedback mechanism in regulating proteasome homeostasis

dDsk2 regulates H2Bub1 and RNA polymerase II pausing at dHP1c complex target genes

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