Systematic analysis of the binding behaviour of UHRF1 towards different methyl- and carboxylcytosine modification patterns at CpG dyads
Open Access
- 21 February 2020
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 15 (2), e0229144
- https://doi.org/10.1371/journal.pone.0229144
Abstract
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.Funding Information
- Deutsche Forschungsgemeinschaft (SFB 1035/A10 and SFB749/C08)
- Deutsche Forschungsgemeinschaft (SFB 1064/A17 and SFB 1243/A01)
- Deutsche Forschungsgemeinschaft (CIPSM)
- Deutsche Forschungsgemeinschaft (CIPSM)
- Deutsche Forschungsgemeinschaft (CA198/10-1)
- Technische Universität München (IGSSE)
- Max-Planck-Gesellschaft (IMPRS-LS)
- Max-Planck-Gesellschaft (IMPRS-LS)
- Deutsche Forschungsgemeinschaft (GRK1721)
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