Hypoxia re-programs 2′-O-Me modifications on ribosomal RNA

Metge, Brandon J.; Kammerud, Sarah C.; Pruitt, Hawley C.; Shevde, Lalita A.; Samant, Rajeev S.

doi:10.1016/j.isci.2020.102010

Cited by 20 publications

(28 citation statements)

References 75 publications

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“…Interestingly, ERK regulates ribosome biogenesis and has multiple intracellular locations including the nucleolus [ 25 , 44 ]. We analyzed nucleolar extracts from SUM159 cells (control as well as treated with fisetin and geraldol) for levels of active nucleolar ERK.…”

Section: Resultsmentioning

confidence: 99%

“…Overall, our investigations revealed negative impacts of fisetin and geraldol on rRNA biogenesis. The details of the impacts of inhibitory effect of flavonoids on DNA-dependent DNA and RNA polymerases have been noticed before [ 25 , 30 ]. These previous studies were more focused on RNA Pol II.…”

Section: Discussionmentioning

confidence: 99%

“…rRNA synthesis was measured as a readout of 5-Fluorouridine (FUrd) incorporation into nascent rRNA transcripts, as previously described [ 25 , 33 ]. Briefly, 100,000 cells were seeded onto 22 × 22 glass coverslips (Fisher Scientific) and allowed to attach overnight.…”

Section: Methodsmentioning

confidence: 99%

“…For example, damaged nucleoli play a role in Parkinson’s disease, Alzheimer’s disease, and cardiovascular disease [ 19 – 21 ]. The nucleolus is most widely recognized as the site for ribosome biogenesis but also plays key roles in DNA damage repair, the regulation of gene expression, and response to cellular stress [ 22 – 25 ]. Cancer cells have been found to contain larger and more numerous nucleoli than normal cells [ 23 , 26 – 29 ].…”

Section: Introductionmentioning

confidence: 99%

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Novel role of the dietary flavonoid fisetin in suppressing rRNA biogenesis

Kammerud

Metge

Elhamamsy

et al. 2021

Laboratory Investigation

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The nucleolus of a cell is a critical cellular compartment that is responsible for ribosome biogenesis and plays a central role in tumor progression. Fisetin, a nutraceutical, is a naturally occurring flavonol from the flavonoid group of polyphenols that has anti-cancer effects. Fisetin negatively impacts several signaling pathways that support tumor progression. However, effect of fisetin on the nucleolus and its functions were unknown. We observed that fisetin is able to physically enter the nucleolus. In the nucleolus, RNA polymerase I (RNA Pol I) mediates the biogenesis of ribosomal RNA. Thus, we investigated the impacts of fisetin on the nucleolus. We observed that breast tumor cells treated with fisetin show a 20–30% decreased nucleolar abundance per cell and a 30–60% downregulation of RNA Pol I transcription activity, as well as a 50–70% reduction in nascent rRNA synthesis, depending on the cell line. Our studies show that fisetin negatively influences MAPK/ERK pathway to impair RNA Pol I activity and rRNA biogenesis. Functionally, we demonstrate that fisetin acts synergistically (CI = 0.4) with RNA Pol I inhibitor, BMH-21 and shows a noteworthy negative impact (60% decrease) on lung colonization of breast cancer cells. Overall, our findings highlight the potential of ribosomal RNA (rRNA) biogenesis as a target for secondary prevention and possible treatment of metastatic disease.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Novel role of the dietary flavonoid fisetin in suppressing rRNA biogenesis

Kammerud

Metge

Elhamamsy

et al. 2021

Laboratory Investigation

Self Cite

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“…Finally, a few pieces of evidence suggest that cellular stresses could also impact 2 Ome. Hence, Metge and colleagues investigated the effect of hypoxia on ribosome biogenesis in T47D and MCF10 breast cancer cell lines and found that not only does hypoxia up-regulate RNA pol I activity and rRNA synthesis compared to normoxia but also modifies 2 Ome of seven out of fourteen sites measured by RTL-qPCR [65]. Interestingly, ribosomes bound to the IRES located in the 5 UTR of VEGF-C mRNA displayed distinct 2 Ome patterns in hypoxia compared to normoxia, therefore suggesting that VEGF-C mRNA could be translated by a distinct pool of ribosomes upon changes in oxygen supply, with potential consequences during tumorigenesis.…”

Section: Rrna 2 Ome Variability In Physio-pathological Contextsmentioning

confidence: 99%

2′O-Ribose Methylation of Ribosomal RNAs: Natural Diversity in Living Organisms, Biological Processes, and Diseases

Jaafar

Paraqindes

Gabut

et al. 2021

Cells

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Recent findings suggest that ribosomes, the translational machineries, can display a distinct composition depending on physio-pathological contexts. Thanks to outstanding technological breakthroughs, many studies have reported that variations of rRNA modifications, and more particularly the most abundant rRNA chemical modification, the rRNA 2′O-ribose methylation (2′Ome), intrinsically occur in many organisms. In the last 5 years, accumulating reports have illustrated that rRNA 2′Ome varies in human cell lines but also in living organisms (yeast, plant, zebrafish, mouse, human) during development and diseases. These rRNA 2′Ome variations occur either within a single cell line, organ, or patient’s sample (i.e., intra-variability) or between at least two biological conditions (i.e., inter-variability). Thus, the ribosomes can tolerate the absence of 2′Ome at some specific positions. These observations question whether variations in rRNA 2′Ome could provide ribosomes with particular translational regulatory activities and functional specializations. Here, we compile recent studies supporting the heterogeneity of ribosome composition at rRNA 2′Ome level and provide an overview of the natural diversity in rRNA 2′Ome that has been reported up to now throughout the kingdom of life. Moreover, we discuss the little evidence that suggests that variations of rRNA 2′Ome can effectively impact the ribosome activity and contribute to the etiology of some human diseases.

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Decoding the ribosome's hidden language: rRNA modifications as key players in cancer dynamics and targeted therapies

Cui,

Zheng,

Lin

et al. 2024

Clinical & Translational Med

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Ribosomal RNA (rRNA) modifications, essential components of ribosome structure and function, significantly impact cellular proteomics and cancer biology. These chemical modifications transcend structural roles, critically shaping ribosome functionality and influencing cellular protein profiles. In this review, the mechanisms by which rRNA modifications regulate both rRNA functions and broader cellular physiological processes are critically discussed. Importantly, by altering the translational output, rRNA modifications can shift the cellular equilibrium towards oncogenesis, thus playing a key role in cancer development and progression. Moreover, a special focus is placed on the functions of mitochondrial rRNA modifications and their aberrant expression in cancer, an area with profound implications yet largely uncharted. Dysregulation in these modifications can lead to metabolic dysfunction and apoptosis resistance, hallmark traits of cancer cells. Furthermore, the current challenges and future perspectives in targeting rRNA modifications are highlighted as a therapeutic approach for cancer treatment. In conclusion, rRNA modifications represent a frontier in cancer research, offering novel insights and therapeutic possibilities. Understanding and harnessing these modifications can pave the way for breakthroughs in cancer treatment, potentially transforming the approach to combating this complex disease.

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Hypoxia re-programs 2′-O-Me modifications on ribosomal RNA

Cited by 20 publications

References 75 publications

Novel role of the dietary flavonoid fisetin in suppressing rRNA biogenesis

Novel role of the dietary flavonoid fisetin in suppressing rRNA biogenesis

2′O-Ribose Methylation of Ribosomal RNAs: Natural Diversity in Living Organisms, Biological Processes, and Diseases

Decoding the ribosome's hidden language: rRNA modifications as key players in cancer dynamics and targeted therapies

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