Enzymatic Hydroxylation and Excision of Extended 5-Methylcytosine Analogues.
DNA cytosine-5 methylation
DNA glycosylase
TET dioxygenase
epigenetic regulation
radical intermediate
Journal
Journal of molecular biology
ISSN: 1089-8638
Titre abrégé: J Mol Biol
Pays: Netherlands
ID NLM: 2985088R
Informations de publication
Date de publication:
20 11 2020
20 11 2020
Historique:
received:
24
06
2020
revised:
05
10
2020
accepted:
08
10
2020
pubmed:
17
10
2020
medline:
6
3
2021
entrez:
16
10
2020
Statut:
ppublish
Résumé
Methylation of cytosine to 5-methylcytosine (mC) is a prevalent reversible epigenetic mark in vertebrates established by DNA methyltransferases (MTases); the methylation mark can be actively erased via a multi-step demethylation mechanism involving oxidation by Ten-eleven translocation (TET) enzyme family dioxygenases, excision of the latter oxidation products by thymine DNA (TDG) or Nei-like 1 (NEIL1) glycosylases followed by base excision repair to restore the unmodified state. Here we probed the activity of the mouse TET1 (mTET1) and Naegleria gruberi TET (nTET) oxygenases with DNA substrates containing extended derivatives of the 5-methylcytosine carrying linear carbon chains and adjacent unsaturated CC bonds. We found that the nTET and mTET1 enzymes were active on modified mC residues in single-stranded and double-stranded DNA in vitro, while the extent of the reactions diminished with the size of the extended group. Iterative rounds of nTET hydroxylations of ssDNA proceeded with high stereo specificity and included not only the natural alpha position but also the adjoining carbon atom in the extended side chain. The regioselectivity of hydroxylation was broken when the reactive carbon was adjoined with an sp
Identifiants
pubmed: 33065111
pii: S0022-2836(20)30588-X
doi: 10.1016/j.jmb.2020.10.011
pmc: PMC7763475
pii:
doi:
Substances chimiques
DNA-Binding Proteins
0
Proto-Oncogene Proteins
0
TET1 protein, mouse
0
5-Methylcytosine
6R795CQT4H
Cytosine
8J337D1HZY
DNA
9007-49-2
DNA Glycosylases
EC 3.2.2.-
Neil1 protein, mouse
EC 3.2.2.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6157-6167Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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