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Comparative Analysis of the Activity of the Polymorphic Variants of Human Uracil-DNA-Glycosylases SMUG1 and MBD4

  • ENZYMOLOGY OF DNA REPAIR SYSTEMS
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Abstract

The human N-glycosylases SMUG1 and MBD4 catalyze the removal of uracil residues from DNA resulting from cytosine deamination or replication errors. For polymorphic variants of SMUG1 (G90C, P240H, N244S, N248Y) and the MBD4cat catalytic domain (S470L, G507S, R512W, H557D), the structures of enzyme-substrate complexes were obtained by molecular dynamic simulation. It was experimentally found that the SNP variants of SMUG1, N244S and N248Y, had increased catalytic activity compared to the wild-type enzyme, probably due to the acceleration of the dissociation of the enzyme–product complex and an increase in the enzyme turnover rate. All other SNP variants of SMUG1 (G90C, P240H) and MBD4cat, in which amino acid substitutions disrupted the substrate binding region and/or active site, had significantly lower catalytic activity than the wild-type enzymes.

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Funding

This work was supported by grant no. 16-14-10038 from the Russian Science Foundation and partial support from budgetary funding (no. АААА-А17-117020210022-4) to ensure routine maintenance of the equipment.

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Authors and Affiliations

  1. Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences, 630090, Novosibirsk, Russia

    I. V. Alekseeva, A. S. Bakman, D. A. Iakovlev, N. A. Kuznetsov & O. S. Fedorova

  2. Department of Natural Sciences, Novosibirsk State University, 630090, Novosibirsk, Russia

    A. S. Bakman

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  1. I. V. Alekseeva
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  2. A. S. Bakman
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  3. D. A. Iakovlev
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  4. N. A. Kuznetsov
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Correspondence to N. A. Kuznetsov or O. S. Fedorova.

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The authors declare they have no conflict of interest. This study does not contain any research involving humans or animals as research objects.

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Alekseeva, I.V., Bakman, A.S., Iakovlev, D.A. et al. Comparative Analysis of the Activity of the Polymorphic Variants of Human Uracil-DNA-Glycosylases SMUG1 and MBD4. Mol Biol 55, 241–251 (2021). https://doi.org/10.1134/S0026893321020035

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  • DOI: https://doi.org/10.1134/S0026893321020035

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