Structural basis for hydroxymethylcytosine recognition by the SRA domain of UHRF2

Mol Cell. 2014 Jun 5;54(5):879-86. doi: 10.1016/j.molcel.2014.04.003. Epub 2014 May 8.

Abstract

Methylated cytosine of CpG dinucleotides in vertebrates may be oxidized by Tet proteins, a process that can lead to DNA demethylation. The predominant oxidation product, 5-hydroxymethylcytosine (5hmC), has been implicated in embryogenesis, cell differentiation, and human diseases. Recently, the SRA domain of UHRF2 (UHRF2-SRA) has been reported to specifically recognize 5hmC, but how UHRF2 recognizes this modification is unclear. Here we report the structure of UHRF2-SRA in complex with a 5hmC-containing DNA. The structure reveals that the conformation of a phenylalanine allows the formation of an optimal 5hmC binding pocket, and a hydrogen bond between the hydroxyl group of 5hmC and UHRF2-SRA is critical for their preferential binding. Further structural and biochemical analyses unveiled the role of SRA domains as a versatile reader of modified DNA, and the knowledge should facilitate further understanding of the biological function of UHRF2 and the comprehension of DNA hydroxymethylation in general.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Methylcytosine / analogs & derivatives
  • Binding Sites
  • Crystallography, X-Ray
  • Cytosine / analogs & derivatives
  • Cytosine / chemistry
  • Humans
  • Hydrogen Bonding
  • Models, Molecular
  • Oligonucleotides / chemistry
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Ubiquitin-Protein Ligases / chemistry*

Substances

  • Oligonucleotides
  • 5-hydroxymethylcytosine
  • 5-Methylcytosine
  • Cytosine
  • UHRF2 protein, human
  • Ubiquitin-Protein Ligases

Associated data

  • PDB/4PW5
  • PDB/4PW6
  • PDB/4PW7