DNA Sequence Recognition of Human CXXC Domains and Their Structural Determinants

Chao Xu; Ke Liu; Ming Lei; Ally Yang; Yanjun Li; Timothy R Hughes; Jinrong Min

doi:10.1016/j.str.2017.11.022

DNA Sequence Recognition of Human CXXC Domains and Their Structural Determinants

Structure. 2018 Jan 2;26(1):85-95.e3. doi: 10.1016/j.str.2017.11.022. Epub 2017 Dec 21.

Authors

Chao Xu¹, Ke Liu¹, Ming Lei¹, Ally Yang², Yanjun Li¹, Timothy R Hughes², Jinrong Min³

Affiliations

¹ Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.
² Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada.
³ Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: jr.min@utoronto.ca.

PMID: 29276034
DOI: 10.1016/j.str.2017.11.022

Abstract

The CXXC domain, first identified as the reader of unmodified CpG dinucleotide, plays important roles in epigenetic regulation by targeting various activities to CpG islands. Here we systematically measured and compared the DNA-binding selectivities of all known human CXXC domains by different binding assays, and complemented the existing function-based classification of human CXXC domains with a classification based on their DNA selectivities. Through a series of crystal structures of CXXC domains with DNA ligands, we unravel the molecular mechanisms of how these CXXC domains, including single CXXC domains and tandem CXXC-PHD domains, recognize distinct DNA ligands, which further supports our classification of human CXXC domains and also provides insights into selective recruitment of chromatin modifiers to their respective targets via CXXC domains recognizing different genomic DNA sequences. Our study facilitates the understanding of the relationship between the DNA-binding specificities of the CXXC proteins and their biological functions.

Keywords: CFP1; CXXC domain; CpG island; DNA methylation; DNMT1; KDM2A; MLL; TET1; epigenetics; histone methylation.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Amino Acid Sequence
Binding Sites
Cloning, Molecular
CpG Islands
Crystallography, X-Ray
DNA / chemistry*
DNA / genetics
DNA / metabolism
DNA-Binding Proteins / chemistry*
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Epigenesis, Genetic
Escherichia coli / genetics
Escherichia coli / metabolism
F-Box Proteins / chemistry*
F-Box Proteins / genetics
F-Box Proteins / metabolism
Gene Expression
Genetic Vectors / chemistry
Genetic Vectors / metabolism
Humans
Jumonji Domain-Containing Histone Demethylases / chemistry*
Jumonji Domain-Containing Histone Demethylases / genetics
Jumonji Domain-Containing Histone Demethylases / metabolism
Mixed Function Oxygenases / chemistry*
Mixed Function Oxygenases / genetics
Mixed Function Oxygenases / metabolism
Models, Molecular
Neoplasm Proteins / chemistry*
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism
Protein Binding
Protein Conformation, alpha-Helical
Protein Conformation, beta-Strand
Protein Interaction Domains and Motifs
Protein Isoforms / chemistry
Protein Isoforms / genetics
Protein Isoforms / metabolism
Proto-Oncogene Proteins / chemistry*
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism
Recombinant Proteins / chemistry
Recombinant Proteins / genetics
Recombinant Proteins / metabolism
Sequence Alignment
Sequence Homology, Amino Acid
Trans-Activators

Substances

CXXC1 protein, human
DNA-Binding Proteins
F-Box Proteins
FBXL19 protein, human
KMT2D protein, human
Neoplasm Proteins
Protein Isoforms
Proto-Oncogene Proteins
Recombinant Proteins
Trans-Activators
DNA
Mixed Function Oxygenases
TET1 protein, human
Jumonji Domain-Containing Histone Demethylases
KDM2A protein, human