Recognition of modification status on a histone H3 tail by linked histone reader modules of the epigenetic regulator UHRF1

Multiple covalent modifications on a histone tail are often recognized by linked histone reader modules. UHRF1 [ubiquitin-like, containing plant homeodomain (PHD) and really interesting new gene (RING) finger domains 1], an essential factor for maintenance of DNA methylation, contains linked two-histone reader modules, a tandem Tudor domain and a PHD finger, tethered by a 17-aa linker, and has been implicated to link histone modifications and DNA methylation. Here, we present the crystal structure of the linked histone reader modules of UHRF1 in complex with the amino-terminal tail of histone H3. Our structural and biochemical data provide the basis for combinatorial readout of unmodified Arg-2 (H3-R2) and methylated Lys-9 (H3-K9) by the tandem tudor domain and the PHD finger. The structure reveals that the intermodule linker plays an essential role in the formation of a histone H3–binding hole between the reader modules by making extended contacts with the tandem tudor domain. The histone H3 tail fits into the hole by adopting a compact fold harboring a central helix, which allows both of the reader modules to simultaneously recognize the modification states at H3-R2 and H3-K9. Our data also suggest that phosphorylation of a linker residue can modulate the relative position of the reader modules, thereby altering the histone H3–binding mode. This finding implies that the linker region plays a role as a functional switch of UHRF1 involved in multiple regulatory pathways such as maintenance of DNA methylation and transcriptional repression.

[1]  V. Kuznetsov,et al.  Symmetric dimethylation of H3R2 is a newly identified histone mark that supports euchromatin maintenance , 2012, Nature Structural &Molecular Biology.

[2]  J. Jakoncic,et al.  UHRF1 double tudor domain and the adjacent PHD finger act together to recognize K9me3-containing histone H3 tail. , 2012, Journal of molecular biology.

[3]  Guohong Li,et al.  Structural basis for site-specific reading of unmodified R2 of histone H3 tail by UHRF1 PHD finger , 2011, Cell Research.

[4]  D. Patel,et al.  PHD finger recognition of unmodified histone H3R2 links UHRF1 to regulation of euchromatic gene expression. , 2011, Molecular cell.

[5]  D. Patel,et al.  ATRX ADD domain links an atypical histone methylation recognition mechanism to human mental-retardation syndrome. , 2011, Nature structural & molecular biology.

[6]  Thomas A. Milne,et al.  Recognition of a Mononucleosomal Histone Modification Pattern by BPTF via Multivalent Interactions , 2011, Cell.

[7]  Shili Duan,et al.  Recognition of Multivalent Histone States Associated with Heterochromatin by UHRF1 Protein* , 2011, The Journal of Biological Chemistry.

[8]  S. Robson,et al.  Nucleosome-Interacting Proteins Regulated by DNA and Histone Methylation , 2010, Cell.

[9]  D. Patel,et al.  TRIM24 links a noncanonical histone signature to breast cancer , 2010, Nature.

[10]  Ming-Ming Zhou,et al.  Mechanism and Regulation of Acetylated Histone Binding by the Tandem PHD Finger of DPF3b , 2010, Nature.

[11]  H. Leonhardt,et al.  The multi-domain protein Np95 connects DNA methylation and histone modification , 2009, Nucleic acids research.

[12]  M. Unoki,et al.  Drug discovery targeting epigenetic codes: the great potential of UHRF1, which links DNA methylation and histone modifications, as a drug target in cancers and toxoplasmosis. , 2009, Biochemical pharmacology.

[13]  M. Shirakawa,et al.  Structural basis for recognition of H3K4 methylation status by the DNA methyltransferase 3A ATRX–DNMT3–DNMT3L domain , 2009, EMBO reports.

[14]  A. Bax,et al.  TALOS+: a hybrid method for predicting protein backbone torsion angles from NMR chemical shifts , 2009, Journal of biomolecular NMR.

[15]  H. Cedar,et al.  Linking DNA methylation and histone modification: patterns and paradigms , 2009, Nature Reviews Genetics.

[16]  Helena Santos-Rosa,et al.  Distinct transcriptional outputs associated with mono- and dimethylated histone H3 arginine 2 , 2009, Nature Structural &Molecular Biology.

[17]  Jinrong Min,et al.  Structure and function of histone methylation binding proteins. , 2009, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[18]  E. Kinoshita,et al.  Separation and detection of large phosphoproteins using Phos-tag SDS-PAGE , 2009, Nature Protocols.

[19]  Yusuke Nakamura,et al.  Recognition of hemi-methylated DNA by the SRA protein UHRF1 by a base-flipping mechanism , 2008, Nature.

[20]  C. Arrowsmith,et al.  Structural basis for recognition of hemi-methylated DNA by the SRA domain of human UHRF1 , 2008, Nature.

[21]  S. Jacobsen,et al.  The SRA domain of UHRF1 flips 5-methylcytosine out of the DNA helix , 2008, Nature.

[22]  Michael Q. Zhang,et al.  Combinatorial patterns of histone acetylations and methylations in the human genome , 2008, Nature Genetics.

[23]  Dustin E. Schones,et al.  Genome-wide approaches to studying chromatin modifications , 2008, Nature Reviews Genetics.

[24]  P. Wright,et al.  Overexpression of post-translationally modified peptides in Escherichia coli by co-expression with modifying enzymes. , 2008, Protein expression and purification.

[25]  G. Sheldrick.  A short history of SHELX. , 2008, Acta crystallographica. Section A, Foundations of crystallography.

[26]  K. Mitsuya,et al.  The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA , 2007, Nature.

[27]  Dinshaw J. Patel,et al.  Multivalent engagement of chromatin modifications by linked binding modules , 2007, Nature Reviews Molecular Cell Biology.

[28]  Sean D. Taverna,et al.  How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers , 2007, Nature Structural &Molecular Biology.

[29]  J. Qin,et al.  ICBP90, a Novel Methyl K9 H3 Binding Protein Linking Protein Ubiquitination with Heterochromatin Formation , 2007, Molecular and Cellular Biology.

[30]  Jürg Bähler,et al.  Arginine methylation at histone H3R2 controls deposition of H3K4 trimethylation , 2007, Nature.

[31]  A. Brunger.  Version 1.2 of the Crystallography and NMR system , 2007, Nature Protocols.

[32]  S. Jacobsen,et al.  UHRF1 Plays a Role in Maintaining DNA Methylation in Mammalian Cells , 2007, Science.

[33]  F. Forneris,et al.  Structural Basis of LSD1-CoREST Selectivity in Histone H3 Recognition* , 2007, Journal of Biological Chemistry.

[34]  Randy J. Read,et al.  Phaser crystallographic software , 2007, Journal of applied crystallography.

[35]  A. Burlingame,et al.  The Site-Specific Installation of Methyl-Lysine Analogs into Recombinant Histones , 2007, Cell.

[36]  Paul Schanda,et al.  Very fast two-dimensional NMR spectroscopy for real-time investigation of dynamic events in proteins on the time scale of seconds. , 2005, Journal of the American Chemical Society.

[37]  Fei Long,et al.  REFMAC5 dictionary: organization of prior chemical knowledge and guidelines for its use. , 2004, Acta crystallographica. Section D, Biological crystallography.

[38]  Kevin Cowtan,et al.  research papers Acta Crystallographica Section D Biological , 2005 .

[39]  C. Bronner,et al.  Phosphorylation of ICBP90 by protein kinase A enhances topoisomerase IIalpha expression. , 2004, Biochemical and biophysical research communications.

[40]  Wolfgang Fischle,et al.  Binary switches and modification cassettes in histone biology and beyond , 2003, Nature.

[41]  Randy J Read,et al.  Electronic Reprint Biological Crystallography Phenix: Building New Software for Automated Crystallographic Structure Determination Biological Crystallography Phenix: Building New Software for Automated Crystallographic Structure Determination , 2022 .

[42]  C. Allis,et al.  Translating the Histone Code , 2001, Science.

[43]  Karl Mechtler,et al.  Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins , 2001, Nature.

[44]  C. Allis,et al.  Signaling to Chromatin through Histone Modifications , 2000, Cell.

[45]  C. Allis,et al.  The language of covalent histone modifications , 2000, Nature.

[46]  Z. Otwinowski,et al.  Processing of X-ray diffraction data collected in oscillation mode. , 1997, Methods in enzymology.

[47]  C. Allis,et al.  Histone Acetylation and Chromatin Assembly: A Single Escort, Multiple Dances? , 1996, Cell.

[48]  S. Grzesiek,et al.  NMRPipe: A multidimensional spectral processing system based on UNIX pipes , 1995, Journal of biomolecular NMR.

[49]  J M Thornton,et al.  LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions. , 1995, Protein engineering.

[50]  J. Thornton,et al.  PROCHECK: a program to check the stereochemical quality of protein structures , 1993 .

[51]  Dmitri I. Svergun,et al.  Determination of the regularization parameter in indirect-transform methods using perceptual criteria , 1992 .

[52]  Adrian Bird,et al.  The essentials of DNA methylation , 1992, Cell.

[53]  O. Glatter,et al.  19 – Small-Angle X-ray Scattering , 1973 .

[54]  B. Matthews.  Some crystal forms of bovine chymotrypsinogen B and chymotrypsinogen A. , 1968, Journal of molecular biology.

[55]  W. Ehrenberg,et al.  Small-Angle X-Ray Scattering , 1952, Nature.