Recognition of hemi-methylated DNA by UHRF1

Objective

Cytosine methylation of CpG dinucleotide sequence is an epigenetic mark on the DNA that regulates gene expression, chromatin structure, and genome stability. Patterns of DNA methylation propagate with fidelity greater than 99% and their stable inheritance for more than 80 cell divisions. This robustness is essential as evidenced by the observation that cancer cells commonly exhibit aberrant methylation patterns. Inheritance and maintenance of methylation patterns are mediated by Dnmt1 during chromosome replication and repair. A crucial step in this process is the ability to distinguish hemi-methylated from either unmethylated or symmetrically di-methylated CpG sequences. Recently, it was shown that the protein UHRF1 recruits Dnmt1 to hemi-methylated CpG sites. The interaction between UHRF1 and hemi-methylated DNA involves the flipping of the methylcytosine out of the DNA helix as revealed by three different crystal structures. Using molecular dynamics simulations, the proposed research is aimed at answering the following questions: (I) What is the energetic basis that allows UHRF1 to discriminate between binding to hemi-methylated DNA versus binding to unmethylated or symmetrically di-methylated DNA? In particular, a disfavored binding to unmethylated DNA can arise due to a cavity at the location of the 'missing' methyl group. Half of the atoms surrounding this cavity are hydrophilic with potential of forming hydrogen bonds. Whether this space is taken up by a water molecule or whether it is 'dry' and the consequences on the UHRF1-DNA binding constant, will be investigated. (II) What is the flip-out mechanism of hemi-methylated methylcytosine? Does UHRF1 play an active role in the flipping event? The process of methylating the target cytosine on the complementary strand by Dnmt1 also involves base flipping. How does the flipped methylcytosine, interacting with UHRF1, influence the barrier and propensity for flipping the target cytosine to be methylated?

Fields of science (EuroSciVoc)

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• engineering and technology materials engineering crystals
• natural sciences biological sciences genetics DNA
• natural sciences biological sciences biochemistry biomolecules proteins
• natural sciences biological sciences genetics chromosomes
• natural sciences biological sciences genetics genomes

Programme(s)

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• FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)

Topic(s)

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• FP7-PEOPLE-2009-RG - Marie Curie Action: "Reintegration Grants"

Call for proposal

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FP7-PEOPLE-2009-RG
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Funding Scheme

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MC-IRG - International Re-integration Grants (IRG)

Coordinator