6u17 › Citations

Excision of 5-Carboxylcytosine by Thymine DNA Glycosylase.

Pidugu LS, Dai Q, Malik SS, Pozharski E, Drohat AC
J Am Chem Soc 141 18851-18861 (2019)
Related entries: 6u15, 6u16

Cited: 15 times
EuropePMC logo PMID: 31693361

Abstract

5-Methylcytosine (mC) is an epigenetic mark that is written by methyltransferases, erased through passive and active mechanisms, and impacts transcription, development, diseases including cancer, and aging. Active DNA demethylation involves TET-mediated stepwise oxidation of mC to 5-hydroxymethylcytosine, 5-formylcytosine (fC), or 5-carboxylcytosine (caC), excision of fC or caC by thymine DNA glycosylase (TDG), and subsequent base excision repair. Many elements of this essential process are poorly defined, including TDG excision of caC. To address this problem, we solved high-resolution structures of human TDG bound to DNA with cadC (5-carboxyl-2'-deoxycytidine) flipped into its active site. The structures unveil detailed enzyme-substrate interactions that mediate recognition and removal of caC, many involving water molecules. Importantly, two water molecules contact a carboxylate oxygen of caC and are poised to facilitate acid-catalyzed caC excision. Moreover, a substrate-dependent conformational change in TDG modulates the hydrogen bond interactions for one of these waters, enabling productive interaction with caC. An Asn residue (N191) that is critical for caC excision is found to contact N3 and N4 of caC, suggesting a mechanism for acid-catalyzed base excision that features an N3-protonated form of caC but would be ineffective for C, mC, or hmC. We also investigated another Asn residue (N140) that is catalytically essential and strictly conserved in the TDG-MUG enzyme family. A structure of N140A-TDG bound to cadC DNA provides the first high-resolution insight into how enzyme-substrate interactions, including water molecules, are impacted by depleting the conserved Asn, informing its role in binding and addition of the nucleophilic water molecule.

Articles - 6u17 mentioned but not cited (2)

  1. Excision of 5-Carboxylcytosine by Thymine DNA Glycosylase. Pidugu LS, Dai Q, Malik SS, Pozharski E, Drohat AC. J Am Chem Soc 141 18851-18861 (2019)
  2. Interaction of Thymine DNA Glycosylase with Oxidised 5-Methyl-cytosines in Their Amino- and Imino-Forms. Volkenandt S, Beierlein F, Imhof P. Molecules 26 5728 (2021)


Reviews citing this publication (2)

  1. The base excision repair process: comparison between higher and lower eukaryotes. Hindi NN, Elsakrmy N, Ramotar D. Cell Mol Life Sci 78 7943-7965 (2021)
  2. Computational investigations on target-site searching and recognition mechanisms by thymine DNA glycosylase during DNA repair process. Wang L, Song K, Yu J, Da LT. Acta Biochim Biophys Sin (Shanghai) 54 796-806 (2022)

Articles citing this publication (11)

  1. TET-TDG Active DNA Demethylation at CpG and Non-CpG Sites. DeNizio JE, Dow BJ, Serrano JC, Ghanty U, Drohat AC, Kohli RM. J Mol Biol 433 166877 (2021)
  2. Atomic resolution of short-range sliding dynamics of thymine DNA glycosylase along DNA minor-groove for lesion recognition. Tian J, Wang L, Da LT. Nucleic Acids Res 49 1278-1293 (2021)
  3. Oxidized Derivatives of 5-Methylcytosine Alter the Stability and Dehybridization Dynamics of Duplex DNA. Sanstead PJ, Ashwood B, Dai Q, He C, Tokmakoff A. J Phys Chem B 124 1160-1174 (2020)
  4. 5-Hydroxymethyl-, 5-Formyl- and 5-Carboxydeoxycytidines as Oxidative Lesions and Epigenetic Marks. Schelter F, Kirchner A, Traube FR, Müller M, Steglich W, Carell T. Chemistry 27 8100-8104 (2021)
  5. 5-Carboxylcytosine and Cytosine Protonation Distinctly Alter the Stability and Dehybridization Dynamics of the DNA Duplex. Ashwood B, Sanstead PJ, Dai Q, He C, Tokmakoff A. J Phys Chem B 124 627-640 (2020)
  6. Intragenomic Decarboxylation of 5-Carboxy-2'-deoxycytidine. Kamińska E, Korytiaková E, Reichl A, Müller M, Carell T. Angew Chem Int Ed Engl 60 23207-23211 (2021)
  7. Structural Insights into the Mechanism of Base Excision by MBD4. Pidugu LS, Bright H, Lin WJ, Majumdar C, Van Ostrand RP, David SS, Pozharski E, Drohat AC. J Mol Biol 433 167097 (2021)
  8. Chemical and enzymatic modifications of 5-methylcytosine at the intersection of DNA damage, repair, and epigenetic reprogramming. Baljinnyam T, Sowers ML, Hsu CW, Conrad JW, Herring JL, Hackfeld LC, Sowers LC. PLoS One 17 e0273509 (2022)
  9. Rapid excision of oxidized adenine by human thymine DNA glycosylase. Servius HW, Pidugu LS, Sherman ME, Drohat AC. J Biol Chem 299 102756 (2023)
  10. DNA Methyltransferases and DNA Damage. Sarkies P. Adv Exp Med Biol 1389 349-361 (2022)
  11. Recent Advances on DNA Base Flipping: A General Mechanism for Writing, Reading, and Erasing DNA Modifications. Ren R, Horton JR, Hong S, Cheng X. Adv Exp Med Biol 1389 295-315 (2022)


Quick links