Kinetic Milestones of Damage Recognition by DNA Glycosylases of the Helix-Hairpin-Helix Structural Superfamily

Kuznetsov, Nikita А.; Fedorova, Olga S.

doi:10.1007/978-3-030-41283-8_1

Cited by 13 publications

(9 citation statements)

References 102 publications

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“…Many DNA glycosylases have been structurally characterized to understand how damaged DNA bases are found and detected among numerous unmodified bases ( Brooks et al, 2013 ). To solve this problem, we have performed pre–steady-state kinetic analyses of conformational changes in DNA glycosylases and in DNA substrates during their interactions ( Kuznetsov and Fedorova, 2016 , 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Lesion Recognition and Cleavage of Damage-Containing Quadruplexes and Bulged Structures by DNA Glycosylases

Кузнецова

Fedorova

Kuznetsov

2020

Front. Cell Dev. Biol.

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Human telomeres as well as more than 40% of human genes near the promoter regions have been found to contain the sequence that may form a G-quadruplex structure. Other non-canonical DNA structures comprising bulges, hairpins, or bubbles may have a functionally important role during transcription, replication, or recombination. The guanine-rich regions of DNA are hotspots of oxidation that forms 7,8-dihydro-8-oxoguanine, thymine glycol, and abasic sites: the lesions that are handled by the base excision repair pathway. Nonetheless, the features of DNA repair processes in non-canonical DNA structures are still poorly understood. Therefore, in this work, a comparative analysis of the efficiency of the removal of a damaged nucleotide from various G-quadruplexes and bulged structures was performed using endonuclease VIII-like 1 (NEIL1), human 8-oxoguanine-DNA glycosylase (OGG1), endonuclease III (NTH1), and prokaryotic formamidopyrimidine-DNA glycosylase (Fpg), and endonuclease VIII (Nei). All the tested enzymes were able to cleave damage-containing bulged DNA structures, indicating their important role in the repair process when single-stranded DNA and intermediate non–B-form structures such as bubbles and bulges are formed. Nevertheless, our results suggest that the ability to cleave damaged quadruplexes is an intrinsic feature of members of the H2tH structural family, suggesting that these enzymes can participate in the modulation of processes controlled by the formation of quadruplex structures in genomic DNA.

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Section: Discussionmentioning

confidence: 99%

Lesion Recognition and Cleavage of Damage-Containing Quadruplexes and Bulged Structures by DNA Glycosylases

Кузнецова

Fedorova

Kuznetsov

2020

Front. Cell Dev. Biol.

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“…Biochemical and structural data on E. coli AlkA provide insights into its alkylated base recognition and removal [43][44][45][46][47][48], suggesting that E. coli AlkA is a well-characterized alkylated DNA glycosylase. Structural data show that AlkA is a structural homolog of endonuclease III [49], possessing a signature DNA-binding motif that comprises a helix-hairpin-helix (HhH) with the consensus sequence Leu/Phe-Pro-Gly-Val/Ile-Gly, followed by an invariant Asp ∼20 residues later [50].…”

Section: Discussionmentioning

confidence: 99%

Biochemical characterization and mutational studies of a novel 3-methlyadenine DNA glycosylase II from the hyperthermophilic Thermococcus gammatolerans

et al. 2021

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The hyperthermophilic and radioresistant euryarchaeon Thermococcus gammatolerans encodes a putative 3-methlyadenine DNA glycosylase II (Tg-AlkA).Herein, we report biochemical characterization and catalytic mechanism of Tg-AlkA.The recombinant Tg-AlkA can excise hypoxanthine (Hx) and 1-methlyadenine (1-meA) from dsDNA with varied efficiencies at high temperature. Notably, Tg-AlkA is a bi-functional glycosylase, which is sharply distinct from all the reported AlkAs.Biochemical data show that the optimal temperature and pH of Tg-AlkA for removing Hx from dsDNA are ca.70°C and ca.7.0-8.0, respectively. Furthermore, the Tg-AlkA activity is independent of a divalent metal ion, and Mg 2+ stimulates the Tg-AlkA activity whereas other divalent ions inhibit the enzyme activity with varied degrees.Mutational studies show that the Tg-AlkA W204A and D223A mutants abolish completely the excision activity, thereby suggesting that residues W204 and D223 are involved in catalysis. Surprisingly, the mutations of W204, D223, Y139 and W256 to alanine in Tg-AlkA lead to the increased affinity for binding DNA substrate with varied degrees, suggesting that these residues are flexible for conformational change of the enzyme. Therefore, Tg-AlkA is a novel AlkA that can remove Hx and 1-meA from dsDNA, thus providing insights into repair of deaminated and alkylated bases in DNA from hyperthermophilic Thermococcus.

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“…Another basis for substrate recognition may be related to differences in the efficiency of abasic-site eversion, which is dependent on the nature of the opposite base and/or on local stability of the damaged region in DNA. According to the multiple studies [48,49] on interactions of DNA repair enzymes with their specific site, the common mechanism of damage recognition that ensures high substrate specificity can be subdivided into several steps: the bending of damaged DNA by the enzyme, eversion of the damaged nucleotide from the double helix and verification of the damaged base in the active site of the enzyme through the formation of specific contacts.…”

Section: Discussionmentioning

confidence: 99%

Common Kinetic Mechanism of Abasic Site Recognition by Structurally Different Apurinic/Apyrimidinic Endonucleases

Кузнецова

Senchurova

Ищенко

et al. 2021

IJMS

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Apurinic/apyrimidinic (AP) endonucleases Nfo (Escherichia coli) and APE1 (human) represent two conserved structural families of enzymes that cleave AP-site–containing DNA in base excision repair. Nfo and APE1 have completely different structures of the DNA-binding site, catalytically active amino acid residues and catalytic metal ions. Nonetheless, both enzymes induce DNA bending, AP-site backbone eversion into the active-site pocket and extrusion of the nucleotide located opposite the damage. All these stages may depend on local stability of the DNA duplex near the lesion. Here, we analysed effects of natural nucleotides located opposite a lesion on catalytic-complex formation stages and DNA cleavage efficacy. Several model DNA substrates that contain an AP-site analogue [F-site, i.e., (2R,3S)-2-(hydroxymethyl)-3-hydroxytetrahydrofuran] opposite G, A, T or C were used to monitor real-time conformational changes of the tested enzymes during interaction with DNA using changes in the enzymes’ intrinsic fluorescence intensity mainly caused by Trp fluorescence. The extrusion of the nucleotide located opposite F-site was recorded via fluorescence intensity changes of two base analogues. The catalytic rate constant slightly depended on the opposite-nucleotide nature. Thus, structurally different AP endonucleases Nfo and APE1 utilise a common strategy of damage recognition controlled by enzyme conformational transitions after initial DNA binding.

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Kinetic Milestones of Damage Recognition by DNA Glycosylases of the Helix-Hairpin-Helix Structural Superfamily

Cited by 13 publications

References 102 publications

Lesion Recognition and Cleavage of Damage-Containing Quadruplexes and Bulged Structures by DNA Glycosylases

Lesion Recognition and Cleavage of Damage-Containing Quadruplexes and Bulged Structures by DNA Glycosylases

Biochemical characterization and mutational studies of a novel 3-methlyadenine DNA glycosylase II from the hyperthermophilic Thermococcus gammatolerans

Common Kinetic Mechanism of Abasic Site Recognition by Structurally Different Apurinic/Apyrimidinic Endonucleases

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