Letter

Nature 455, 826-829 (9 October 2008) | doi:10.1038/nature07280; Received 17 March 2008; Accepted 23 July 2008; Published online 3 September 2008

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

Hideharu Hashimoto1, John R. Horton1, Xing Zhang1, Magnolia Bostick2, Steven E. Jacobsen2,3 & Xiaodong Cheng1

  1. Department of Biochemistry, Emory University School of Medicine, 1510 Clifton Road, Atlanta, Georgia 30322, USA
  2. Department of Molecular Cell and Developmental Biology,
  3. Hughes Medical Institute, University of California, Los Angeles, 621 Charles E. Young Dr. South, Los Angeles, California 90095, USA

Correspondence to: Xiaodong Cheng1 Correspondence and requests for materials should be addressed to X.C. (Email: xcheng@emory.edu).

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.

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