uracil base
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2021 ◽  
Author(s):  
Alexis A Jourdain ◽  
Owen S Skinner ◽  
Akinori Kawakami ◽  
Russel P. Goodman ◽  
Hongying Shen ◽  
...  

Glucose is vital for life, serving both as a source of energy and as a carbon building block for growth. When glucose availability is limiting, alternative nutrients must be harnessed. To identify mechanisms by which cells can tolerate complete loss of glucose, we performed nutrient-sensitized, genome-wide genetic screening and growth assays of 482 pooled PRISM cancer cell lines. We report that catabolism of uridine enables the growth of cells in the complete absence of glucose. While previous studies have shown that the uracil base of uridine can be salvaged to support growth in the setting of mitochondrial electron transport chain deficiency (1), our work shows that the ribose moiety of uridine can be salvaged via a pathway we call uridinolysis defined as: [1] the phosphorylytic cleavage of uridine by UPP1/2 into uracil and ribose-1-phosphate (R1P), [2] the conversion of R1P into fructose-6-P and glyceraldehyde-3-P by PGM2 and the non-oxidative branch of the pentose phosphate pathway (non-oxPPP), and [3] their glycolytic utilization to fuel ATP production, biosynthesis and gluconeogenesis. Intriguingly, we report that uridine nucleosides derived from RNA are also a substrate for uridinolysis and that RNA can support growth in glucose-limited conditions. Our results underscore the malleability of central carbon metabolism and raise the provocative hypothesis that RNA can also serve as a potential storage for energy.


PLoS ONE ◽  
2020 ◽  
Vol 15 (7) ◽  
pp. e0235012
Author(s):  
Mesfin Meshesha ◽  
Alexandre Esadze ◽  
Junru Cui ◽  
Natela Churgulia ◽  
Sushil Kumar Sahu ◽  
...  

2020 ◽  
Author(s):  
Mesfin Meshesha ◽  
Alexandre Esadze ◽  
Junru Cui ◽  
Natela Churgulia ◽  
Sushil Kumar Sahu ◽  
...  

AbstractNon-dividing cells of the myeloid lineage such as monocytes and macrophages are target cells of HIV that have low dNTP pool concentrations and elevated levels of dUTP, which leads to frequent incorporation of dUMP opposite to A during reverse transcription (“uracilation”). One factor determining the fate of dUMP in proviral DNA is the host cell uracil base excision repair (UBER) system. Here we explore the relative UBER capacity of monocytes (MC) and monocyte-derived macrophages (MDM) and the fate of integrated uracilated viruses in both cell types to understand the implications of viral dUMP on HIV diversification and infectivity. We find that monocytes are almost completely devoid of functional UBER, while macrophages are mainly deficient in the initial enzyme uracil DNA glycosylase (hUNG2). Accordingly, dUMP persists in viral DNA during the lifetime of a MC and can only be removed after differentiation of MC into MDM. Overexpression of human uracil DNA glycosylase in MDM prior to infection resulted in rapid removal of dUMP from HIV cDNA and near complete depletion of dUMP-containing viral copies. This finding establishes that the low hUNG2 expression level in these cells limits UBER but that hUNG2 is restrictive against uracilated viruses. In contrast, overexpression of hUNG2 after viral integration did not accelerate the excision of uracils, suggesting that they may poorly accessible in the context of chromatin. We found that viral DNA molecules with incorporated dUMP contained unique (+) strand transversion mutations that were not observed when dUMP was absent (G→T, T→A, T→G, A→C). These observations and other considerations suggest that dUMP introduces errors predominantly during (-) strand synthesis when the template is RNA. These mutations may arise from the increased mispairing and duplex destabilizing effects of dUMP relative to dTMP during reverse transcription. Overall, the likelihood of producing a functional virus from in vitro infection of MC is about 50-fold and 300-fold reduced as compared to MDM and activated T cells. The results implicate viral dUMP incorporation in MC and MDM as a potential viral diversification and restriction pathway during human HIV infection.


2020 ◽  
Author(s):  
Mesfin Meshesha ◽  
Alexandre Esadze ◽  
Junru Cui ◽  
Natela Churgulia ◽  
Sushil Kumar Sahu ◽  
...  

Abstract Background Non-dividing cells of the myeloid lineage such as monocytes and macrophages are target cells of HIV that have low dNTP pool concentrations and elevated levels of dUTP, which leads to frequent incorporation of dUMP opposite to A during reverse transcription (“uracilation”). One factor determining the fate of dUMP in proviral DNA is the host cell uracil base excision repair (UBER) system. Here we explore the relative UBER capacity of monocytes (MC) and monocyte-derived macrophages (MDM) and the fate of integrated uracilated viruses in both cell types to understand the implications of viral dUMP on HIV diversification and infectivity.Results We find that monocytes are almost completely devoid of functional UBER, while macrophages are mainly deficient in the initial enzyme uracil DNA glycosylase (hUNG2). Accordingly, dUMP persists in viral DNA during the lifetime of a MC and can only be removed after differentiation of MC into MDM. Overexpression of human uracil DNA glycosylase in MDM prior to infection resulted in rapid removal of dUMP from HIV cDNA and near complete depletion of dUMP-containing viral copies. This finding establishes that the low hUNG2 expression level in these cells limits UBER but that hUNG2 is restrictive against uracilated viruses. In contrast, overexpression of hUNG2 after viral integration did not accelerate the excision of uracils, suggesting that they may poorly accessible in the context of chromatin. We found that viral DNA molecules with incorporated dUMP contained unique (+) strand transversion mutations that were not observed when dUMP was absent (G→T, T→A, T→G, A→C). These observations and other considerations suggest that dUMP introduces errors predominantly during (-) strand synthesis when the template is RNA. These mutations may arise from the increased mispairing and duplex destabilizing effects of dUMP relative to dTMP during reverse transcription. Overall, the likelihood of producing a functional virus from in vitro infection of MC is about 50-fold and 300-fold reduced as compared to MDM and activated T cells.Conclusions The results implicate viral dUMP incorporation in MC and MDM as a potential viral diversification and restriction pathway during human HIV infection.


2019 ◽  
Vol 23 (07n08) ◽  
pp. 797-812 ◽  
Author(s):  
Sonja Merkaš ◽  
Mladen Žinić ◽  
Régis Rein ◽  
Nathalie Solladié

During the past years, we focused on exerting control over the position and distance of porphyrins along our specifically designed oligonucleotidic scaffold. Indeed, in naturally occurring light-harvesting complexes, biopolymer scaffolds hold pigments at intermolecular distances that optimize photon capture, electronic coupling, and energy transfer. To this end, four uridine-porphyrin conjugates (a monomer, a dimer, a tetramer and an octamer) were subjected to a comprehensive conformational analysis by using NMR spectroscopy. The collected NOE NMR data highlighted characteristic and strong interactions indicating that the glycosidic angle between the ribose and uracil base is anti. In order to further investigate the conformation of this family of molecules, NMR experiments were carried out at variable temperatures. At low temperature, the signals of the porphyrinic protons decoalesce, showing two sets of [Formula: see text]-pyrrolic protons. Similar observations are made for signals corresponding to sugar moieties and especially the H1′ protons, indicating molecular motions within our porphyrin-uridin arrays. These results testify in favor of the existence of a dynamic process between C3′-endo and C2′-endo conformations.


Genes ◽  
2018 ◽  
Vol 9 (7) ◽  
pp. 324 ◽  
Author(s):  
Naďa Špačková ◽  
Kamila Réblová
Keyword(s):  

2018 ◽  
Vol 115 (19) ◽  
pp. 4921-4926 ◽  
Author(s):  
Eddy Sanchai Thientosapol ◽  
Daniel Bosnjak ◽  
Timothy Durack ◽  
Igor Stevanovski ◽  
Michelle van Geldermalsen ◽  
...  

Activation-induced deaminase (AID) initiates hypermutation of Ig genes in activated B cells by converting C:G into U:G base pairs. G1-phase variants of uracil base excision repair (BER) and mismatch repair (MMR) then deploy translesion polymerases including REV1 and Pol η, which exacerbates mutation. dNTP paucity may contribute to hypermutation, because dNTP levels are reduced in G1 phase to inhibit viral replication. To derestrict G1-phase dNTP supply, we CRISPR-inactivated SAMHD1 (which degrades dNTPs) in germinal center B cells. Samhd1 inactivation increased B cell virus susceptibility, increased transition mutations at C:G base pairs, and substantially decreased transversion mutations at A:T and C:G base pairs in both strands. We conclude that SAMHD1’s restriction of dNTP supply enhances AID’s mutagenicity and that the evolution of Ig hypermutation included the repurposing of antiviral mechanisms based on dNTP starvation.


2018 ◽  
Vol 54 (30) ◽  
pp. 3715-3718 ◽  
Author(s):  
Yuanqi Ding ◽  
Lei Xie ◽  
Xinyi Yao ◽  
Wei Xu
Keyword(s):  
The Real ◽  

The real-space evidence of Watson–Crick and Hoogsteen Adenine–uracil base pairs on Au(111).


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