Identification of a prototypical single-stranded uracil DNA glycosylase from Listeria innocua

Li, Jing; Yang, Ye; Guevara, José Luís Alfredo Mora; Cao, Weiguo

doi:10.1016/j.dnarep.2017.07.001

Cited by 8 publications

(2 citation statements)

References 56 publications

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“…The DNA glycosylase cleavage assays for DR0022 were performed at optimized temperature 37 °C for 60 min in a 10‐μL reaction mixture containing 10 n m oligonucleotide substrate [43], an indicated amount of glycosylase, 20 m m citric acid and phosphate buffer with the indicated pH (4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0) [44], 1 m m dithiothreitol, and 1 m m EDTA. The resulting abasic sites were cleaved by incubation at 95 °C for 5 min after adding 1 μL of 1 n NaOH.…”

Section: Methodsmentioning

confidence: 99%

DR0022 from Deinococcus radiodurans is an acid uracil‐DNA glycosylase

Yang

Chang

et al. 2022

The FEBS Journal

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Uracil‐DNA glycosylase (UDG) initiates base excision repair (BER) by removing damaged or modified nucleobases during DNA repair or mammalian demethylation. The UDG superfamily consists of at least six families with a variety of catalytic specificities and functions. Deinococcus radiodurans, an extreme radiation resistant bacterium, contains multiple members of UDG enzymes within its genome. The present study reveals that the putative protein, DR0022, is a uracil‐DNA glycosylase that requires acidic conditions for its glycosylase activity, which is the first case of such an enzyme within the UDG superfamily. The key residues in the catalytic motifs are investigated by biochemical, enzyme kinetics, and de novo structural prediction, as well as molecular modeling analyses. The structural and catalytic roles of several distinct residues are discussed in light of predicted and modeled DR0022 glycosylase structures. The spontaneous mutation rate analysis performed in a dr0022 deficient D. radiodurans strain indicated that the dr0022 gene plays a role in mutation prevention. Furthermore, survival rate analysis in a dr0022 deficient D. radiodurans strain demonstrated its role in stress resistance, including γ‐irradiation. Additionally, the novel acid UDG activity in relationship to its in vivo roles is discussed. This work underscores the functional diversity in the UDG superfamily.

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Section: Methodsmentioning

confidence: 99%

DR0022 from Deinococcus radiodurans is an acid uracil‐DNA glycosylase

Yang

Chang

et al. 2022

The FEBS Journal

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“…The UDG superfamily has at least 6 major branches, with general conservation of motifs important to ligand binding, substrate selectivity and catalysis, as well as overall architectural similarities especially at the catalytic centre (comprehensively reviewed in [29]). New variants of almost all UDG families are regularly reported in the literature [30,31], including variants of family 1 enzymes (i.e. Ungs) [32,33].…”

Section: Ung Structure and Mechanism A Slight Comparisonmentioning

confidence: 99%

Targeting Uracil-DNA Glycosylases for Therapeutic Outcomes Using Insights from Virus Evolution

Savva

2019

Future Med. Chem.

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Ung-type uracil-DNA glycosylases are frontline defenders of DNA sequence fidelity in bacteria, plants, and animals; Ungs also directly assist both innate and humoral immunity. Critically important in viral pathogenesis, whether acting for or against viral DNA persistence, Ungs also have therapeutic relevance to cancer, microbial, and parasitic diseases. Ung catalytic specificity is uniquely conserved, yet selective antiviral drugging of the Ung catalytic pocket is tractable. However, more promising precision therapy approaches present themselves via insights from viral strategies, including sequestration or adaptation of Ung for non-canonical roles. A universal Ung inhibition mechanism, converged upon by unrelated viruses, could also inform design of compounds to inhibit specific distinct Ungs. Extrapolating current developments, the character of such novel chemical entities is proposed. Executive Summary • Introduction Ungs are essential enzymes at the forefront of pathogenic states, both defending cells and being co-opted by pathogens. • Ung structure and mechanism Ung is an exquisitely specific catalytic domain, but pre-catalytic variations promise specificity between targeting the host enzyme and pathogenic variants. • Origins and significance of uracil-substituted DNA in pathogenesis Viruses have evolved to silence, or co-opt Ung to facilitate pathogenic states. Understanding these origins allows search for novel Ung-interacting proteins. Knowledge of Ung-interacting protein interfaces can facilitate drug discovery. • Motivations and contexts for therapeutic interventions targeting Ung Understanding the significance of Ung in diverse pathogenic states permits suitable intervention to be designed and implemented. • Convergence on a universal Ung-inhibitory mechanism by unrelated virus proteins Natural protein-protein interactions that irreversibly inhibit Ung activity, by convergence on a common mechanism have independently evolved at least 3 times from different protein architectures. The naturally evolved inhibitor proteins do not target uracil specificity of Ung. • Synthetic selective Ung inhibition and future trends Drug design centred upon uracil-analogues has shown specificity is achievable. Compounds featuring uracil and hydrophobic tails are not ideal drug candidate molecules. Compounds targeting Ung protein-protein interactions have shown selective potency against poxviruses. • Conclusions Eschewing uracil-specificity to emulate features of natural protein-protein interactions, promises novelty in selective drug discovery to target Ungs in pathogenic states. Herpesviruses (g-/ EBV, KSHV) Elongated/structured pre-catalytic loop is essential to replication [34,35]. Poxviruses [vaccinia] Divergent features/ variant pre-catalytic loop, resistant to phage-mediated inhibition; potent PPI inhibitors identified [26-28]. Mycobacterium tuberculosis Atypical catalytic structure, weakened phage-mediated inhibition [36,37]. Plasmodium falciparum Divergent sequence; uracil-analogue inhibitors identified [38]. * Pe...

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Screening of glycosylase activity on oxidative derivatives of methylcytosine: Pedobacter heparinus SMUG2 as a formylcytosine- and carboxylcytosine-DNA glycosylase

Chang

Yang

et al. 2022

DNA Repair

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Identification of a prototypical single-stranded uracil DNA glycosylase from Listeria innocua

Cited by 8 publications

References 56 publications

DR0022 from Deinococcus radiodurans is an acid uracil‐DNA glycosylase

DR0022 from Deinococcus radiodurans is an acid uracil‐DNA glycosylase

Targeting Uracil-DNA Glycosylases for Therapeutic Outcomes Using Insights from Virus Evolution

Screening of glycosylase activity on oxidative derivatives of methylcytosine: Pedobacter heparinus SMUG2 as a formylcytosine- and carboxylcytosine-DNA glycosylase

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