Sphingosine, a Modulator of Human Translesion DNA Polymerase Activity

Kamath-Loeb, Ashwini S.; Balakrishna, Sharath; Whittington, Dale; Shen, Jiang; Emond, Mary J.; Okabe, Takayoshi; Masutani, Chikahide; Hanaoka, Fumio; Nishimura, Susumu; Loeb, Lawrence A.

doi:10.1074/jbc.m114.570242

Cited by 9 publications

(5 citation statements)

References 44 publications

(55 reference statements)

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“…Sphingosine also regulates nuclear lipid signaling as it has been shown to bind the nuclear receptor, Steroidogenic Factor-1, that mediates steroid biosynthesis and primase that regulates synthesis of RNA primers (Simbulan et al 1994;Urs et al 2006). Recently, sphingosine has been found to activate translesion DNA polymerase to promote cell proliferation (Kamath-Loeb et al 2014). Moreover, the cellular effects of sphingosine are cell type and cell context dependent.…”

Section: Sphingolipid Metabolismmentioning

confidence: 98%

Resveratrol and its oligomers: modulation of sphingolipid metabolism and signaling in disease

et al. 2014

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Resveratrol, a natural compound endowed with multiple health-promoting effects, has received much attention given its potential for the treatment of cardiovascular, inflammatory, neurodegenerative, metabolic and age-related diseases. However, the translational potential of resveratrol has been limited by its specificity, poor bioavailability and uncertain toxicity. In recent years, there has been an accumulation of evidence demonstrating that resveratrol modulates sphingolipid metabolism. Moreover, resveratrol forms higher order oligomers that exhibit better selectivity and potency in modulating sphingolipid metabolism. This review evaluates the evidence supporting the modulation of sphingolipid metabolism and signaling as a mechanism of action underlying the therapeutic efficacy of resveratrol and oligomers in diseases, such as cancer.

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Section: Sphingolipid Metabolismmentioning

confidence: 98%

Resveratrol and its oligomers: modulation of sphingolipid metabolism and signaling in disease

et al. 2014

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“…First, in vitro experiments suggested that some lipid species, such as oleic acid, may directly bind to DNA (Zhdanov et al, 2002), which could have significant impacts on gene expression but is not currently supported by data obtained under physiological conditions (Fernandes et al, 2018). There is also some evidence supporting an effect of specific lipid species on DNA polymerase activity (Novello et al, 1975;Kamath-Loeb et al, 2014). Interestingly, although the mechanism remains unclear, changes in palmitate concentration in vitro appear to regulate the expression of neuronal genes and increased intracellular palmitate results in increased differentiation of neural precursor cells into neurons (Ardah et al, 2018).…”

Section: Lipids and Regulation Of The Transcriptome And Epigenomementioning

confidence: 99%

Lipid Mediated Regulation of Adult Stem Cell Behavior

Clémot

Demarco

Jones

2020

Front. Cell Dev. Biol.

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Adult stem cells constitute an important reservoir of self-renewing progenitor cells and are crucial for maintaining tissue and organ homeostasis. The capacity of stem cells to self-renew or differentiate can be attributed to distinct metabolic states, and it is now becoming apparent that metabolism plays instructive roles in stem cell fate decisions. Lipids are an extremely vast class of biomolecules, with essential roles in energy homeostasis, membrane structure and signaling. Imbalances in lipid homeostasis can result in lipotoxicity, cell death and diseases, such as cardiovascular disease, insulin resistance and diabetes, autoimmune disorders and cancer. Therefore, understanding how lipid metabolism affects stem cell behavior offers promising perspectives for the development of novel approaches to control stem cell behavior either in vitro or in patients, by modulating lipid metabolic pathways pharmacologically or through diet. In this review, we will first address how recent progress in lipidomics has created new opportunities to uncover stem-cell specific lipidomes. In addition, genetic and/or pharmacological modulation of lipid metabolism have shown the involvement of specific pathways, such as fatty acid oxidation (FAO), in regulating adult stem cell behavior. We will describe and compare findings obtained in multiple stem cell models in order to provide an assessment on whether unique lipid metabolic pathways may commonly regulate stem cell behavior. We will then review characterized and potential molecular mechanisms through which lipids can affect stem cell-specific properties, including self-renewal, differentiation potential or interaction with the niche. Finally, we aim to summarize the current knowledge of how alterations in lipid homeostasis that occur as a consequence of changes in diet, aging or disease can impact stem cells and, consequently, tissue homeostasis and repair.

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“…This technique has been applied to study a number of systems including D-3-phosphoglycerate dehydrogenase, 45 beta-site amyloid precursor protein-cleaving enzyme, 46 ATP-phosphoribosyl-transferase, 47 DNA polymerase γ , 48 and HIV-RT. 49,50 …”

Section: Resultsmentioning

confidence: 99%

“…Presteady-state kinetic analysis of enzyme inhibition is a powerful approach for determining which step or steps are affected by a given inhibitor. This technique has been applied to study a number of systems including D-3-phosphoglycerate dehydrogenase, 45 beta-site amyloid precursor protein-cleaving enzyme, 46 ATP-phosphoribosyltransferase, 47 DNA polymerase γ, 48 and HIV-RT. 49,50 Presteady-state analysis was carried out using a rapid quench apparatus to further characterize the mechanism of inhibition of pol β and pol λ.…”

Section: ′-G a A G A C T G G T G A A G A C T T G A G T A C A G G T C ...mentioning

confidence: 99%

Honokiol Inhibits DNA Polymerases β and λ and Increases Bleomycin Sensitivity of Human Cancer Cells

Gowda

Suo

Spratt

2017

Chem. Res. Toxicol.

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A major concept to sensitize cancer cells to DNA damaging agents is by inhibiting proteins in the DNA repair pathways. X-family DNA polymerases play critical roles in both base excision repair (BER) and nonhomologous end joining (NHEJ). In this study, we examined the effectiveness of honokiol to inhibit human DNA polymerase β (pol β), which is involved in BER, and DNA polymerase λ (pol λ), which is involved in NHEJ. Kinetic analysis with purified polymerases showed that honokiol inhibited DNA polymerase activity. The inhibition mode for the polymerases was a mixed-function noncompetitive inhibition with respect to the substrate, dCTP. The X-family polymerases, pol β and pol λ, were slightly more sensitive to inhibition by honokiol based on the Ki value of 4.0 μM for pol β, and 8.3 μM for pol λ, while the Ki values for pol η and Kf were 20 and 26 μM, respectively. Next we extended our studies to determine the effect of honokiol on the cytotoxicity of bleomycin and temozolomide in human cancer cell lines A549, MCF7, PANC-1, UACC903, and normal blood lymphocytes (GM12878). Bleomycin causes both single strand DNA damage that is repaired by BER and double strand breaks that are repaired by NHEJ, while temozolomide causes methylation damage repaired by BER and O6-alkylguanine-DNA alkyltransferase. The greatest effects were found with the honokiol and bleomycin combination in MCF7, PANC-1, and UACC903 cells, in which the EC50 values were decreased 10-fold. The temozolomide and honokiol combination was less effective; the EC50 values decreased three-fold due to the combination. It is hypothesized that the greater effect of honokiol on bleomycin is due to inhibition of the repair of the single strand and double strand damage. The synergistic activity shown by the combination of bleomycin and honokiol suggests that they can be used as combination therapy for treatment of cancer, which will decrease the therapeutic dosage and side effects of bleomycin.

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Sphingosine, a Modulator of Human Translesion DNA Polymerase Activity

Cited by 9 publications

References 44 publications

Resveratrol and its oligomers: modulation of sphingolipid metabolism and signaling in disease

Resveratrol and its oligomers: modulation of sphingolipid metabolism and signaling in disease

Lipid Mediated Regulation of Adult Stem Cell Behavior

Honokiol Inhibits DNA Polymerases β and λ and Increases Bleomycin Sensitivity of Human Cancer Cells

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