scholarly journals The NF-κB Nucleolar Stress Response Pathway

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1082
Author(s):  
Hazel C. Thoms ◽  
Lesley A. Stark
Keyword(s):  
Stress Response ◽  
Transcription Initiation ◽  
Critical Role ◽  
Initiation Factor ◽  
Downstream Effector ◽  
Nucleolar Stress ◽  
Transcription Initiation Factor ◽  
Stress Response Pathway ◽  
Regulate Cell Growth ◽  
Polymerase I

The nuclear organelle, the nucleolus, plays a critical role in stress response and the regulation of cellular homeostasis. P53 as a downstream effector of nucleolar stress is well defined. However, new data suggests that NF-κB also acts downstream of nucleolar stress to regulate cell growth and death. In this review, we will provide insight into the NF-κB nucleolar stress response pathway. We will discuss apoptosis mediated by nucleolar sequestration of RelA and new data demonstrating a role for p62 (sequestosome (SQSTM1)) in this process. We will also discuss activation of NF-κB signalling by degradation of the RNA polymerase I (PolI) complex component, transcription initiation factor-IA (TIF-IA (RRN3)), and contexts where TIF-IA-NF-κB signalling may be important. Finally, we will discuss how this pathway is targeted by aspirin to mediate apoptosis of colon cancer cells.

scholarly journals Effects of single-base substitutions within the Acanthamoeba castellanii rRNA promoter on transcription and on binding of transcription initiation factor and RNA polymerase I.

1988 ◽  
Vol 8 (2) ◽  
pp. 747-753 ◽  
Author(s):  
P Kownin ◽  
E Bateman ◽  
M R Paule
Keyword(s):  
Transcription Initiation ◽  
Single Point ◽  
Point Mutations ◽  
Acanthamoeba Castellanii ◽  
Dnase I ◽  
Initiation Factor ◽  
Rrna Gene ◽  
Transcription Initiation Factor ◽  
Polymerase I

Single-point mutations were introduced into the promoter region of the Acanthamoeba castellanii rRNA gene by chemical mutagen treatment of a single-stranded clone in vitro, followed by reverse transcription and cloning of the altered fragment. The promoter mutants were tested for transcription initiation factor (TIF) binding by a template commitment assay plus DNase I footprinting and for transcription by an in vitro runoff assay. Point mutations within the previously identified TIF interaction region (between -20 and -47, motifs A and B) indicated that TIF interacts most strongly with a sequence centered at -29 and less tightly with sequences upstream and downstream. Some alterations of the base sequence closer to the transcription start site (and outside the TIF-protected site) also significantly decreased specific RNA synthesis in vitro. These were within the region which is protected from DNase I digestion by polymerase I, but these mutations did not detectably affect the binding of polymerase to the promoter.

scholarly journals Identification of a novel, NF-κB nucleolar stress response pathway

2017 ◽  
Author(s):  
Jingyu Chen ◽  
Ian T Lobb ◽  
Pierre Morin ◽  
Sonia M Novo ◽  
James Simpson ◽  
...  
Keyword(s):  
Stress Response ◽  
Ex Vivo ◽  
Critical Role ◽  
Rdna Transcription ◽  
Therapeutic Implications ◽  
Stress Effects ◽  
Nucleolar Stress ◽  
Stress Response Pathway ◽  
Cdk4 Inhibition

Abstractp53 as an effector of nucleolar stress is well defined, but p53 independent mechanisms are largely unknown. Like p53, the NF-κB transcription factor plays a critical role in maintaining cellular homeostasis under stress. Many stresses that stimulate NF-κB also disrupt nucleoli. However, the link between nucleolar function and activation of the NF-κB pathway is as yet unknown. Here we demonstrate that siRNA silencing of PolI complex components stimulates NF-κB signalling. Unlike p53 nucleolar stress response, this effect does not appear to be linked to inhibition of rDNA transcription. We show that specific stress stimuli of NF-κB induce degradation of a critical component of the PolI complex, TIF-IA. This degradation precedes activation of the NF-κB pathway and is associated with an atypical nucleolar architecture. It is mimicked by CDK4 inhibition and is dependent upon upstream binding factor (UBF) and p14ARF. We show that blocking stress effects on TIF-IA blocks their ability to activate the NF-κB pathway. Finally, usingex vivoculture, we show a strong correlation between degradation of TIF-IA and activation of NF-κB in freshly resected, human colorectal tumours exposed to the chemopreventative agent, aspirin. Together, our study provides compelling evidence for a new, NF-κB nucleolar stress response pathway that has in vivo relevance and therapeutic implications.

Effects of single-base substitutions within the Acanthamoeba castellanii rRNA promoter on transcription and on binding of transcription initiation factor and RNA polymerase I

1988 ◽  
Vol 8 (2) ◽  
pp. 747-753
Author(s):  
P Kownin ◽  
E Bateman ◽  
M R Paule
Keyword(s):  
Transcription Initiation ◽  
Single Point ◽  
Point Mutations ◽  
Acanthamoeba Castellanii ◽  
Dnase I ◽  
Initiation Factor ◽  
Rrna Gene ◽  
Transcription Initiation Factor ◽  
Polymerase I

Single-point mutations were introduced into the promoter region of the Acanthamoeba castellanii rRNA gene by chemical mutagen treatment of a single-stranded clone in vitro, followed by reverse transcription and cloning of the altered fragment. The promoter mutants were tested for transcription initiation factor (TIF) binding by a template commitment assay plus DNase I footprinting and for transcription by an in vitro runoff assay. Point mutations within the previously identified TIF interaction region (between -20 and -47, motifs A and B) indicated that TIF interacts most strongly with a sequence centered at -29 and less tightly with sequences upstream and downstream. Some alterations of the base sequence closer to the transcription start site (and outside the TIF-protected site) also significantly decreased specific RNA synthesis in vitro. These were within the region which is protected from DNase I digestion by polymerase I, but these mutations did not detectably affect the binding of polymerase to the promoter.

scholarly journals Two RNA Polymerase I Subunits Control the Binding and Release of Rrn3 during Transcription

2007 ◽  
Vol 28 (5) ◽  
pp. 1596-1605 ◽  
Author(s):  
Frédéric Beckouet ◽  
Sylvie Labarre-Mariotte ◽  
Benjamin Albert ◽  
Yukiko Imazawa ◽  
Michel Werner ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Transcription Initiation ◽  
Binding Domain ◽  
Rna Polymerase I ◽  
Initiation Factor ◽  
C Terminus ◽  
Transcription Initiation Factor ◽  
Polymerase I ◽  
Polymerase Mutants

ABSTRACT Rpa34 and Rpa49 are nonessential subunits of RNA polymerase I, conserved in species from Saccharomyces cerevisiae and Schizosaccharomyces pombe to humans. Rpa34 bound an N-terminal region of Rpa49 in a two-hybrid assay and was lost from RNA polymerase in an rpa49 mutant lacking this Rpa34-binding domain, whereas rpa34Δ weakened the binding of Rpa49 to RNA polymerase. rpa34Δ mutants were caffeine sensitive, and the rpa34Δ mutation was lethal in a top1Δ mutant and in rpa14Δ, rpa135(L656P), and rpa135(D395N) RNA polymerase mutants. These defects were shared by rpa49Δ mutants, were suppressed by the overexpression of Rpa49, and thus, were presumably mediated by Rpa49 itself. rpa49 mutants lacking the Rpa34-binding domain behaved essentially like rpa34Δ mutants, but strains carrying rpa49Δ and rpa49-338::HIS3 (encoding a form of Rpa49 lacking the conserved C terminus) had reduced polymerase occupancy at 30°C, failed to grow at 25°C, and were sensitive to 6-azauracil and mycophenolate. Mycophenolate almost fully dissociated the mutant polymerase from its ribosomal DNA (rDNA) template. The rpa49Δ and rpa49-338::HIS3 mutations had a dual effect on the transcription initiation factor Rrn3 (TIF-IA). They partially impaired its recruitment to the rDNA promoter, an effect that was bypassed by an N-terminal deletion of the Rpa43 subunit encoded by rpa43-35,326, and they strongly reduced the release of the Rrn3 initiation factor during elongation. These data suggest a dual role of the Rpa49-Rpa34 dimer during the recruitment of Rrn3 and its subsequent dissociation from the elongating polymerase.

TATA box-binding protein (TBP) is a constituent of the polymerase I-specific transcription initiation factor TIF-IB (SL1) bound to the rRNA promoter and shows differential sensitivity to TBP-directed reagents in polymerase I, II, and III transcription factors

1994 ◽  
Vol 14 (1) ◽  
pp. 597-605
Author(s):  
C A Radebaugh ◽  
J L Matthews ◽  
G K Geiss ◽  
F Liu ◽  
J M Wong ◽  
...  
Keyword(s):  
Transcription Initiation ◽  
Binding Protein ◽  
Acanthamoeba Castellanii ◽  
Differential Sensitivity ◽  
Initiation Factor ◽  
Transcription Initiation Factor ◽  
I Factor ◽  
Tata Box Binding Protein ◽  
Polymerase I

The role of the Acanthamoeba castellanii TATA-binding protein (TBP) in transcription was examined. Specific antibodies against the nonconserved N-terminal domain of TBP were used to verify the presence of TBP in the fundamental transcription initiation factor for RNA polymerase I, TIF-IB, and to demonstrate that TBP is part of the committed initiation complex on the rRNA promoter. The same antibodies inhibit transcription in all three polymerase systems, but they do so differentially. Oligonucleotide competitors were used to evaluate the accessibility of the TATA-binding site in TIF-IB, TFIID, and TFIIIB. The results suggest that insertion of TBP into the polymerase II and III factors is more similar than insertion into the polymerase I factor.

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