scholarly journals Interaction of Thymine DNA Glycosylase with Oxidised 5-Methyl-cytosines in Their Amino- and Imino-Forms

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 5728
Author(s):  
Senta Volkenandt ◽  
Frank Beierlein ◽  
Petra Imhof
Keyword(s):  
Excision Repair ◽  
Conformational Dynamics ◽  
Dna Glycosylase ◽  
Binding Affinities ◽  
Thymine Dna Glycosylase ◽  
Free Dna ◽  
Methyl Cytosine ◽  
Base Excision ◽  
Dynamics Simulations ◽  
Hydrolysis Of

Thymine DNA Glycosylase (TDG) is an enzyme of the base excision repair mechanism and removes damaged or mispaired bases from DNA via hydrolysis of the glycosidic bond. Specificity is of high importance for such a glycosylase, so as to avoid the damage of intact DNA. Among the substrates reported for TDG are mispaired uracil and thymine but also formyl-cytosine and carboxyl-cytosine. Methyl-cytosine and hydroxylmethyl-cytosine are, in contrast, not processed by the TDG enzyme. We have in this work employed molecular dynamics simulations to explore the conformational dynamics of DNA carrying a formyl-cytosine or carboxyl-cytosine and compared those to DNA with the non-cognate bases methyl-cytosine and hydroxylmethyl-cytosine, as amino and imino tautomers. Whereas for the mispairs a wobble conformation is likely decisive for recognition, all amino tautomers of formyl-cytosine and carboxyl-cytosine exhibit the same Watson–Crick conformation, but all imino tautomers indeed form wobble pairs. The conformational dynamics of the amino tautomers in free DNA do not exhibit differences that could be exploited for recognition, and also complexation to the TDG enzyme does not induce any alteration that would indicate preferable binding to one or the other oxidised methyl-cytosine. The imino tautomers, in contrast, undergo a shift in the equilibrium between a closed and a more open, partially flipped state, towards the more open form upon complexation to the TDG enzyme. This stabilisation of the more open conformation is most pronounced for the non-cognate bases methyl-cytosine and hydroxyl-cytosine and is thus not a likely mode for recognition. Moreover, calculated binding affinities for the different forms indicate the imino forms to be less likely in the complexed DNA. These findings, together with the low probability of imino tautomers in free DNA and the indifference of the complexed amino tautomers, suggest that discrimination of the oxidised methyl-cytosines does not take place in the initial complex formation.

scholarly journals Thymine DNA Glycosylase Can Rapidly Excise 5-Formylcytosine and 5-Carboxylcytosine

2011 ◽  
Vol 286 (41) ◽  
pp. 35334-35338 ◽  
Author(s):  
Atanu Maiti ◽  
Alexander C. Drohat
Keyword(s):  
Embryonic Development ◽  
Catalytic Mechanism ◽  
Excision Repair ◽  
Dna Demethylation ◽  
Oxidation Products ◽  
Dna Glycosylase ◽  
Thymine Dna Glycosylase ◽  
Active Demethylation ◽  
Active Dna Demethylation ◽  
Base Excision

Thymine DNA glycosylase (TDG) excises T from G·T mispairs and is thought to initiate base excision repair (BER) of deaminated 5-methylcytosine (mC). Recent studies show that TDG, including its glycosylase activity, is essential for active DNA demethylation and embryonic development. These and other findings suggest that active demethylation could involve mC deamination by a deaminase, giving a G·T mispair followed by TDG-initiated BER. An alternative proposal is that demethylation could involve iterative oxidation of mC to 5-hydroxymethylcytosine (hmC) and then to 5-formylcytosine (fC) and 5-carboxylcytosine (caC), mediated by a Tet (ten eleven translocation) enzyme, with conversion of caC to C by a putative decarboxylase. Our previous studies suggest that TDG could excise fC and caC from DNA, which could provide another potential demethylation mechanism. We show here that TDG rapidly removes fC, with higher activity than for G·T mispairs, and has substantial caC excision activity, yet it cannot remove hmC. TDG excision of fC and caC, oxidation products of mC, is consistent with its strong specificity for excising bases from a CpG context. Our findings reveal a remarkable new aspect of specificity for TDG, inform its catalytic mechanism, and suggest that TDG could protect against fC-induced mutagenesis. The results also suggest a new potential mechanism for active DNA demethylation, involving TDG excision of Tet-produced fC (or caC) and subsequent BER. Such a mechanism obviates the need for a decarboxylase and is consistent with findings that TDG glycosylase activity is essential for active demethylation and embryonic development, as are mechanisms involving TDG excision of deaminated mC or hmC.

scholarly journals The Hepatitis B Virus X Protein Inhibits Thymine DNA Glycosylase Initiated Base Excision Repair

PLoS ONE ◽  
2012 ◽  
Vol 7 (11) ◽  
pp. e48940 ◽  
Author(s):  
Maarten A. A. van de Klundert ◽  
Formijn J. van Hemert ◽  
Hans L. Zaaijer ◽  
Neeltje A. Kootstra
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Dna Glycosylase ◽  
X Protein ◽  
Thymine Dna Glycosylase ◽  
B Virus ◽  
Base Excision

scholarly journals Histone deacetylase SIRT1 modulates and deacetylates DNA base excision repair enzyme thymine DNA glycosylase

2013 ◽  
Vol 456 (1) ◽  
pp. 89-98 ◽  
Author(s):  
Amrita Madabushi ◽  
Bor-Jang Hwang ◽  
Jin Jin ◽  
A-Lien Lu
Keyword(s):  
Dna Repair ◽  
Histone Deacetylase ◽  
Excision Repair ◽  
Dna Glycosylase ◽  
Repair Enzyme ◽  
Repair Gene ◽  
Thymine Dna Glycosylase ◽  
Dna Base Excision Repair ◽  
Dna Repair Gene ◽  
Base Excision

SIRT1 histone deacetylase interacts with the DNA repair enzyme thymine DNA glycosylase (TDG). SIRT1 inhibits TDG expression and deacetylates TDG to modulate TDG activity and substrate specificity. These interactions may mediate DNA repair, gene expression and drug cytotoxicity.

scholarly journals Thymine DNA glycosylase modulates DNA damage response and gene expression by base excision repair-dependent and independent mechanisms

2017 ◽  
Vol 22 (4) ◽  
pp. 392-405 ◽  
Author(s):  
Tomohumi Nakamura ◽  
Kouichi Murakami ◽  
Haruto Tada ◽  
Yoshihiko Uehara ◽  
Jumpei Nogami ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Dna Glycosylase ◽  
Thymine Dna Glycosylase ◽  
Damage Response ◽  
Base Excision

scholarly journals Association of Dnmt3a and thymine DNA glycosylase links DNA methylation with base-excision repair

2006 ◽  
Vol 35 (2) ◽  
pp. 390-400 ◽  
Author(s):  
Ya-Qiang Li ◽  
Ping-Zhu Zhou ◽  
Xiu-Dan Zheng ◽  
Colum P. Walsh ◽  
Guo-Liang Xu
Keyword(s):  
Dna Methylation ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Dna Glycosylase ◽  
Thymine Dna Glycosylase ◽  
Base Excision

scholarly journals Thymine DNA Glycosylase Is Essential for Active DNA Demethylation by Linked Deamination-Base Excision Repair

Cell ◽  
2011 ◽  
Vol 146 (1) ◽  
pp. 67-79 ◽  
Author(s):  
Salvatore Cortellino ◽  
Jinfei Xu ◽  
Mara Sannai ◽  
Robert Moore ◽  
Elena Caretti ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
Dna Demethylation ◽  
Dna Glycosylase ◽  
Thymine Dna Glycosylase ◽  
Active Dna Demethylation ◽  
Base Excision

scholarly journals SUMO-1 regulates the conformational dynamics of Thymine-DNA Glycosylase regulatory domain and competes with its DNA binding activity

2011 ◽  
Vol 12 (1) ◽  
pp. 4 ◽  
Author(s):  
Caroline Smet-Nocca ◽  
Jean-Michel Wieruszeski ◽  
Hélène Léger ◽  
Sebastian Eilebrecht ◽  
Arndt Benecke
Keyword(s):  
Dna Binding ◽  
Conformational Dynamics ◽  
Binding Activity ◽  
Dna Glycosylase ◽  
Regulatory Domain ◽  
Thymine Dna Glycosylase ◽  
Dna Binding Activity

scholarly journals Molecular mechanisms associated with clustered lesion-induced impairment of 8-oxoG recognition by the human glycosylase OGG1

2021 ◽  
Author(s):  
Tao Jiang ◽  
Antonio MONARI ◽  
Elise Dumont ◽  
Emmanuelle Bignon
Keyword(s):  
Protein Interactions ◽  
Molecular Mechanisms ◽  
Excision Repair ◽  
Structural Features ◽  
Repair Pathway ◽  
Dna Lesion ◽  
Damage Response ◽  
Base Excision ◽  
Structural Signature ◽  
Dynamics Simulations

The 8-oxo-7,8-dihydroguanine, referred to as 8-oxoG, is a highly mutagenic DNA lesion that can provoke the appearance of mismatches if it escapes the DNA Damage Response. The specific recognition of its structural signature by the hOGG1 glycosylase is the first step along the Base Excision Repair pathway, that ensures the integrity of the genome by preventing the emergence of mutations. 8-oxoG formation, structural features and repair have been the matter of extensive research and more recently this active field of research expended to the more complicated case of 8-oxoG within clustered lesions. Indeed, the presence of a second lesion within 1 or 2 helix turns can dramatically impact the repair yields of 8-oxoG by glycosylases. In this work, we use mu-range molecular dynamics simulations and machine learning-based post-analysis to explore the molecular mechanisms associated with the recognition of 8-oxoG by hOGG1 when embedded in a multiple lesions site with a mismatch in 5' or 3'. We delineate the stiffening of the DNA-protein interactions upon the presence of the mismatches, and rationalize the much lower repair yields reported with a 5' mismatch by describing the perturbation of 8-oxoG structural features upon addition of an adjacent lesion.

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