Systematic analysis of the binding behaviour of UHRF1 towards different methyl- and carboxylcytosine modification patterns at CpG dyads.
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2020
2020
Historique:
received:
04
09
2019
accepted:
30
01
2020
entrez:
22
2
2020
pubmed:
23
2
2020
medline:
12
5
2020
Statut:
epublish
Résumé
The multi-domain protein UHRF1 is essential for DNA methylation maintenance and binds DNA via a base-flipping mechanism with a preference for hemi-methylated CpG sites. We investigated its binding to hemi- and symmetrically modified DNA containing either 5-methylcytosine (mC), 5-hydroxymethylcytosine (hmC), 5-formylcytosine (fC), or 5-carboxylcytosine (caC). Our experimental results indicate that UHRF1 binds symmetrically carboxylated and hybrid methylated/carboxylated CpG dyads in addition to its previously reported substrates. Complementary molecular dynamics simulations provide a possible mechanistic explanation of how the protein could differentiate between modification patterns. First, we observe different local binding modes in the nucleotide binding pocket as well as the protein's NKR finger. Second, both DNA modification sites are coupled through key residues within the NKR finger, suggesting a communication pathway affecting protein-DNA binding for carboxylcytosine modifications. Our results suggest a possible additional function of the hemi-methylation reader UHRF1 through binding of carboxylated CpG sites. This opens the possibility of new biological roles of UHRF1 beyond DNA methylation maintenance and of oxidised methylcytosine derivates in epigenetic regulation.
Identifiants
pubmed: 32084194
doi: 10.1371/journal.pone.0229144
pii: PONE-D-19-24927
pmc: PMC7034832
doi:
Substances chimiques
5-carboxylcytosine
0
CCAAT-Enhancer-Binding Proteins
0
5-Methylcytosine
6R795CQT4H
Cytosine
8J337D1HZY
Ubiquitin-Protein Ligases
EC 2.3.2.27
Uhrf1 protein, mouse
EC 2.3.2.27
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0229144Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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