Letter

Nature 455, 818-821 (9 October 2008) | doi:10.1038/nature07249; Received 21 March 2008; Accepted 9 July 2008; Published online 3 September 2008

Recognition of hemi-methylated DNA by the SRA protein UHRF1 by a base-flipping mechanism

Kyohei Arita1, Mariko Ariyoshi1, Hidehito Tochio1,2, Yusuke Nakamura3 & Masahiro Shirakawa1,2,4

  1. Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan
  2. Japan Science and Technology Agency, CREST, 4-1-18, Honcho, Kawaguchi-shi, Saitama 332-0012, Japan
  3. Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
  4. RIKEN, Yokohama Institute, Suehirocho, Tsurumi, Yokohama 230-0045, Japan

Correspondence to: Mariko Ariyoshi1Masahiro Shirakawa1,2,4 Correspondence and requests for materials should be addressed to M.S. (Email: shirakawa@moleng.kyoto-u.ac.jp) or M.A. (Email: ma4@eng.mbox.media.kyoto-u.ac.jp).

DNA methylation of CpG dinucleotides is an important epigenetic modification of mammalian genomes and is essential for the regulation of chromatin structure, of gene expression and of genome stability1, 2. Differences in DNA methylation patterns underlie a wide range of biological processes, such as genomic imprinting, inactivation of the X chromosome, embryogenesis, and carcinogenesis3, 4, 5, 6. Inheritance of the epigenetic methylation pattern is mediated by the enzyme DNA methyltransferase 1 (Dnmt1), which methylates newly synthesized CpG sequences during DNA replication, depending on the methylation status of the template strands7, 8. The protein UHRF1 (also known as Np95 and ICBP90) recognizes hemi-methylation sites via a SET and RING-associated (SRA) domain and directs Dnmt1 to these sites9, 10, 11. Here we report the crystal structures of the SRA domain in free and hemi-methylated DNA-bound states. The SRA domain folds into a globular structure with a basic concave surface formed by highly conserved residues. Binding of DNA to the concave surface causes a loop and an amino-terminal tail of the SRA domain to fold into DNA interfaces at the major and minor grooves of the methylation site. In contrast to fully methylated CpG sites recognized by the methyl-CpG-binding domain12, 13, the methylcytosine base at the hemi-methylated site is flipped out of the DNA helix in the SRA–DNA complex and fits tightly into a protein pocket on the concave surface. The complex structure suggests that the successive flip out of the pre-existing methylated cytosine and the target cytosine to be methylated is associated with the coordinated transfer of the hemi-methylated CpG site from UHRF1 to Dnmt1.

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