Dynamics of the Excised Base Release in Thymine DNA Glycosylase During DNA Repair Process

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2017 Dec 19

PMID 29253232

Citations 12

Authors

Lin-Tai Da

Yi Shi

Guodong Ning

Jin Yu

Affiliations

Soon will be listed here.

Abstract

Thymine DNA glycosylase (TDG) initiates base excision repair by cleaving the N-glycosidic bond between the sugar and target base. After catalysis, the release of excised base is a requisite step to terminate the catalytic cycle and liberate the TDG for the following enzymatic reactions. However, an atomistic-level understanding of the dynamics of the product release process in TDG remains unknown. Here, by employing molecular dynamics simulations combined with the Markov State Model, we reveal the dynamics of the thymine release after the excision at microseconds timescale and all-atom resolution. We identify several key metastable states of the thymine and its dominant releasing pathway. Notably, after replacing the TDG residue Gly142 with tyrosine, the thymine release is delayed compared to the wild-type (wt) TDG, as supported by our potential of mean force (PMF) calculations. These findings warrant further experimental tests to potentially trap the excised base in the active site of TDG after the catalysis, which had been unsuccessful by previous attempts. Finally, we extended our studies to other TDG products, including the uracil, 5hmU, 5fC and 5caC bases in order to compare the product release for different targeting bases in the TDG-DNA complex.

Citing Articles

Molecular Mechanisms Underlying the Loop-Closing Dynamics of β-1,4 Galactosyltransferase 1.

Tian J, Jia W, Dong H, Luo X, Gong L, Ren Y J Chem Inf Model. 2024; 65(1):390-401.

PMID: 39737871 PMC: 11734692. DOI: 10.1021/acs.jcim.4c02010.

Metabolomics Analysis as a Tool to Measure Cobalt Neurotoxicity: An In Vitro Validation.

Alanazi I, Alzahrani A, Zughaibi T, Al-Asmari A, Tabrez S, Henderson C Metabolites. 2023; 13(6).

PMID: 37367855 PMC: 10302852. DOI: 10.3390/metabo13060698.

Unveiling the methyl transfer mechanisms in the epigenetic machinery DNMT3A-3 L: A comprehensive study integrating assembly dynamics with catalytic reactions.

Yang W, Zhuang J, Li C, Cheng G Comput Struct Biotechnol J. 2023; 21:2086-2099.

PMID: 36968013 PMC: 10034213. DOI: 10.1016/j.csbj.2023.03.002.

Automated Path Searching Reveals the Mechanism of Hydrolysis Enhancement by T4 Lysozyme Mutants.

Xi K, Zhu L Int J Mol Sci. 2022; 23(23).

PMID: 36498954 PMC: 9736071. DOI: 10.3390/ijms232314628.

Computational investigations on target-site searching and recognition mechanisms by thymine DNA glycosylase during DNA repair process.

Wang L, Song K, Yu J, Da L Acta Biochim Biophys Sin (Shanghai). 2022; 54(6):796-806.

PMID: 35593467 PMC: 9828053. DOI: 10.3724/abbs.2022050.

References

Karplus M, McCammon J . Molecular dynamics simulations of biomolecules. Nat Struct Biol. 2002; 9(9):646-52. DOI: 10.1038/nsb0902-646. View

Cortazar D, Kunz C, Selfridge J, Lettieri T, Saito Y, MacDougall E . Embryonic lethal phenotype reveals a function of TDG in maintaining epigenetic stability. Nature. 2011; 470(7334):419-23. DOI: 10.1038/nature09672. View

Plattner N, Noe F . Protein conformational plasticity and complex ligand-binding kinetics explored by atomistic simulations and Markov models. Nat Commun. 2015; 6:7653. PMC: 4506540. DOI: 10.1038/ncomms8653. View

Zhu L, Sheong F, Zeng X, Huang X . Elucidation of the conformational dynamics of multi-body systems by construction of Markov state models. Phys Chem Chem Phys. 2016; 18(44):30228-30235. DOI: 10.1039/c6cp02545e. View

Yu J, Yool A, Schulten K, Tajkhorshid E . Mechanism of gating and ion conductivity of a possible tetrameric pore in aquaporin-1. Structure. 2006; 14(9):1411-23. DOI: 10.1016/j.str.2006.07.006. View

Coey C, Malik S, Pidugu L, Varney K, Pozharski E, Drohat A . Structural basis of damage recognition by thymine DNA glycosylase: Key roles for N-terminal residues. Nucleic Acids Res. 2016; 44(21):10248-10258. PMC: 5137436. DOI: 10.1093/nar/gkw768. View

Da L, Wang D, Huang X . Dynamics of pyrophosphate ion release and its coupled trigger loop motion from closed to open state in RNA polymerase II. J Am Chem Soc. 2011; 134(4):2399-406. PMC: 3273452. DOI: 10.1021/ja210656k. View

Maiti A, Michelson A, Armwood C, Lee J, Drohat A . Divergent mechanisms for enzymatic excision of 5-formylcytosine and 5-carboxylcytosine from DNA. J Am Chem Soc. 2013; 135(42):15813-22. PMC: 3930231. DOI: 10.1021/ja406444x. View

Wu X, Zhang Y . TET-mediated active DNA demethylation: mechanism, function and beyond. Nat Rev Genet. 2017; 18(9):517-534. DOI: 10.1038/nrg.2017.33. View

10.

He Y, Li B, Li Z, Liu P, Wang Y, Tang Q . Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science. 2011; 333(6047):1303-7. PMC: 3462231. DOI: 10.1126/science.1210944. View

11.

Jensen M, Park S, Tajkhorshid E, Schulten K . Energetics of glycerol conduction through aquaglyceroporin GlpF. Proc Natl Acad Sci U S A. 2002; 99(10):6731-6. PMC: 124471. DOI: 10.1073/pnas.102649299. View

12.

Morgan M, Bennett M, Drohat A . Excision of 5-halogenated uracils by human thymine DNA glycosylase. Robust activity for DNA contexts other than CpG. J Biol Chem. 2007; 282(38):27578-86. PMC: 2818988. DOI: 10.1074/jbc.M704253200. View

13.

Hornak V, Abel R, Okur A, Strockbine B, Roitberg A, Simmerling C . Comparison of multiple Amber force fields and development of improved protein backbone parameters. Proteins. 2006; 65(3):712-25. PMC: 4805110. DOI: 10.1002/prot.21123. View

14.

Ryckbosch S, Wender P, Pande V . Molecular dynamics simulations reveal ligand-controlled positioning of a peripheral protein complex in membranes. Nat Commun. 2017; 8(1):6. PMC: 5431895. DOI: 10.1038/s41467-016-0015-8. View

15.

Da L, Pardo-Avila F, Xu L, Silva D, Zhang L, Gao X . Bridge helix bending promotes RNA polymerase II backtracking through a critical and conserved threonine residue. Nat Commun. 2016; 7:11244. PMC: 4838855. DOI: 10.1038/ncomms11244. View

16.

Wang J, Wolf R, Caldwell J, Kollman P, Case D . Development and testing of a general amber force field. J Comput Chem. 2004; 25(9):1157-74. DOI: 10.1002/jcc.20035. View

17.

Bowman G, Huang X, Pande V . Using generalized ensemble simulations and Markov state models to identify conformational states. Methods. 2009; 49(2):197-201. PMC: 2753735. DOI: 10.1016/j.ymeth.2009.04.013. View

18.

Bowman G, Voelz V, Pande V . Atomistic folding simulations of the five-helix bundle protein λ(6−85). J Am Chem Soc. 2010; 133(4):664-7. PMC: 3043158. DOI: 10.1021/ja106936n. View

19.

Cortazar D, Kunz C, Saito Y, Steinacher R, Schar P . The enigmatic thymine DNA glycosylase. DNA Repair (Amst). 2006; 6(4):489-504. DOI: 10.1016/j.dnarep.2006.10.013. View

20.

Schormann N, Ricciardi R, Chattopadhyay D . Uracil-DNA glycosylases-structural and functional perspectives on an essential family of DNA repair enzymes. Protein Sci. 2014; 23(12):1667-85. PMC: 4253808. DOI: 10.1002/pro.2554. View