AMP-activated protein kinase adapts rRNA synthesis to cellular energy supply

Hoppe, Sven; Bierhoff, Holger; Cado, Ivana; Wéber, Andrea; Tiebe, Marcel; Grummt, Ingrid; Voit, Renate

doi:10.1073/pnas.0909873106

Cited by 186 publications

(163 citation statements)

References 36 publications

Supporting

Mentioning

149

Contrasting

Unclassified

Order By: Relevance

“…The inability to restart transcription after UV (measured by [ 3 H]uridine incorporation) is the hallmark characteristic of CS cells (28). However, rRNA synthesis (which is rather high in growing cells) represents a large fraction of the incorporated [ 3 H]uridine in these studies, and thus results may not be representative of global transcription of type II genes (32). Furthermore, a more recent analysis showed HK genes were repressed after UV in CS-B cells, whereas p53-inducible genes were not (24).…”

Section: Xp-d/cs Cells Display Global Transcriptional Dysregulation Amentioning

confidence: 49%

Sirt1 suppresses RNA synthesis after UV irradiation in combined xeroderma pigmentosum group D/Cockayne syndrome (XP-D/CS) cells

Vélez-Cruz

Zadorin

Coin

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Specific mutations in the XPD subunit of transcription factor IIH result in combined xeroderma pigmentosum (XP)/Cockayne syndrome (CS), a severe DNA repair disorder characterized at the cellular level by a transcriptional arrest following UV irradiation. This transcriptional arrest has always been thought to be the result of faulty transcription-coupled repair. In the present study, we showed that, following UV irradiation, XP-D/CS cells displayed a gross transcriptional dysregulation compared with "pure" XP-D cells or WT cells. Furthermore, global RNA-sequencing analysis showed that XP-D/CS cells repressed the majority of genes after UV, whereas pure XP-D cells did not. By using housekeeping genes as a model, we demonstrated that XP-D/CS cells were unable to reassemble these gene promoters and thus to restart transcription after UV irradiation. Furthermore, we found that the repression of these promoters in XP-D/CS cells was not a simple consequence of deficient repair but rather an active heterochromatinization process mediated by the histone deacetylase Sirt1. Indeed, RNA-sequencing analysis showed that inhibition of and/or silencing of Sirt1 changed the chromatin environment at these promoters and restored the transcription of a large portion of the repressed genes in XP-D/CS cells after UV irradiation. Our work demonstrates that a significant part of the transcriptional arrest displayed by XP-D/CS cells arises as a result of an active repression process and not simply as a result of a DNA repair deficiency. This dysregulation of Sirt1 function that results in transcriptional repression may be the cause of various severe clinical features in patients with XP-D/ CS that cannot be explained by a DNA repair defect.nucleotide excision repair | sirtuins | aging | progeria

show abstract

Section: Xp-d/cs Cells Display Global Transcriptional Dysregulation Amentioning

confidence: 49%

Sirt1 suppresses RNA synthesis after UV irradiation in combined xeroderma pigmentosum group D/Cockayne syndrome (XP-D/CS) cells

Vélez-Cruz

Zadorin

Coin

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Phosphorylation of Rrn3 by kinases linked to nutrient or energy availability, mitogen activation, stress and cell cycle cues modulate its transcriptional initiation activity. These observations led to the proposal that transcription initiation via modulation of Rrn3 activity is the major rate-limiting step for rRNA synthesis in mammalian cells [22,[26][27][28][29][30][31]. This model is supported by a study that utilized live cell imaging combined with computational modeling to analyze the transcription complex dynamics of rDNA transcription regulation during the cell cycle.…”

Section: Accepted Manuscriptmentioning

confidence: 79%

Cell cycle and growth stimuli regulate different steps of RNA polymerase I transcription

Hung

Lesmana

Peck

et al. 2017

Gene

View full text Add to dashboard Cite

, Cell cycle and growth stimuli regulate different steps of RNA polymerase I transcription. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Gene(2016Gene( ), doi: 10.1016Gene( /j.gene.2016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT ACCEPTED MANUSCRIPT A C C E P T E D M A N U S C R I P T A C C E P T E D M A N U S C R I P T 3 AbstractTranscription of the ribosomal RNA genes (rDNA) by RNA Polymerase I (Pol I) is a major control step for ribosome synthesis and is tightly linked to cellular growth.However, the question of whether this process is modulated primarily at the level of transcription initiation or elongation is controversial. Studies in markedly different cell types have identified either initiation or elongation as the major control point. In this study, we have re-examined this question in NIH3T3 fibroblasts using a combination of metabolic labelling of the 47S rRNA, chromatin immunoprecipitation analysis of Pol I and overexpression of the transcription initiation factor Rrn3. Acute manipulation of growth factor levels altered rRNA synthesis rates over 8-fold without changing Pol I loading onto the rDNA. In fact, robust changes in Pol I loading were only observed under conditions where inhibition of rDNA transcription was associated with chronic serum starvation or cell cycle arrest. Overexpression of the transcription initiation factor Rrn3 increased loading of Pol I on the rDNA but failed to enhance rRNA synthesis in either serum starved, serum treated or G0/G1 arrested cells. Together these data suggest that transcription elongation is rate limiting for rRNA synthesis. We propose that transcription initiation is required for rDNA transcription in response to cell cycle cues, whereas elongation controls the dynamic range of rRNA synthesis output in response to acute growth factor modulation.

show abstract

“…AMPK activation causes a p53-dependent cell cycle arrest (Imamura et al 2001) and inhibits essentially all biosynthetic pathways required for cell growth, including synthesis of fatty acids, phospholipids, proteins, and ribosomal RNA (Hardie 2007;Hoppe et al 2009). Thus, AMPK activation would be expected to suppress cell growth and proliferation.…”

Section: Roles Of Ampk In Cancer and In Viral Infectionmentioning

confidence: 99%

Adenosine Monophosphate-Activated Protein Kinase: A Central Regulator of Metabolism with Roles in Diabetes, Cancer, and Viral Infection

Hardie¹

2011

Cold Spring Harbor Symposia on Quantitative Biology

View full text Add to dashboard Cite

Adenosine monophosphate -activated protein kinase (AMPK) is a cellular energy sensor activated by metabolic stresses that inhibit catabolic ATP production or accelerate ATP consumption. Once activated, AMPK switches on catabolic pathways, generating ATP, while inhibiting cell growth and proliferation, thus promoting energy homeostasis. AMPK is activated by the antidiabetic drug metformin, and by many natural products including "nutraceuticals" and compounds used in traditional medicines. Most of these xenobiotics activate AMPK by inhibiting mitochondrial ATP production. AMPK activation by metabolic stress requires the upstream kinase, LKB1, whose tumor suppressor effects may be largely mediated by AMPK. However, many tumor cells appear to have developed mechanisms to reduce AMPK activation and thus escape its growthrestraining effects. A similar phenomenon occurs during viral infection. If we can establish how down-regulation occurs in tumors and virus-infected cells, there may be therapeutic avenues to reverse these effects.

show abstract

AMP-activated protein kinase adapts rRNA synthesis to cellular energy supply

Cited by 186 publications

References 36 publications

Sirt1 suppresses RNA synthesis after UV irradiation in combined xeroderma pigmentosum group D/Cockayne syndrome (XP-D/CS) cells

Sirt1 suppresses RNA synthesis after UV irradiation in combined xeroderma pigmentosum group D/Cockayne syndrome (XP-D/CS) cells

Cell cycle and growth stimuli regulate different steps of RNA polymerase I transcription

Adenosine Monophosphate-Activated Protein Kinase: A Central Regulator of Metabolism with Roles in Diabetes, Cancer, and Viral Infection

Contact Info

Product

Resources

About