The SRA domain of UHRF1 flips 5-methylcytosine out of the DNA helix

Journal Article · Thu Nov 13 04:00:00 EST 2008 · Nature

DOI:https://doi.org/10.1038/nature07280· OSTI ID:1006856

Hashimoto, H; Horton, J R; Zhang, X; Bostick, M; Jacobsen, S; Cheng, X ^[1]

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1. Emory-MED

Maintenance methylation of hemimethylated CpG dinucleotides at DNA replication forks is the key to faithful mitotic inheritance of genomic methylation patterns. UHRF1 (ubiquitin-like, containing PHD and RING finger domains 1) is required for maintenance methylation by interacting with DNA nucleotide methyltransferase 1 (DNMT1), the maintenance methyltransferase, and with hemimethylated CpG, the substrate for DNMT1 (refs 1 and 2). Here we present the crystal structure of the SET and RING-associated (SRA) domain of mouse UHRF1 in complex with DNA containing a hemimethylated CpG site. The DNA is contacted in both the major and minor grooves by two loops that penetrate into the middle of the DNA helix. The 5-methylcytosine has flipped completely out of the DNA helix and is positioned in a binding pocket with planar stacking contacts, Watson-Crick polar hydrogen bonds and van der Waals interactions specific for 5-methylcytosine. Hence, UHRF1 contains a previously unknown DNA-binding module and is the first example of a non-enzymatic, sequence-specific DNA-binding protein domain to use the base flipping mechanism to interact with DNA.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: USDOE
• OSTI ID: 1006856
• Journal Information: Nature, Journal Name: Nature Journal Issue: 10, 2008 Vol. 455
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

08 HYDROGEN
CRYSTAL STRUCTURE
DNA
DNA REPLICATION
HYDROGEN
MAINTENANCE
METHYLATION
NUCLEOTIDES
PROTEINS
SUBSTRATES