DNA methylation is central to such diverse phenomena as restriction and modification in bacteria, repeat induced point-mutation in fungi, and for programming gene expression patterns, embryonic development, and DNA replication in vertebrates. Our long term goal is to understand from a structural standpoint how different classes of DNA methyltransferases work, with specific emphasis on the mechanism of base flipping. The starting point for most of these studies is the structures of the Hhal methyltransferase (a C5-cytosine methyltransfrase) in binary complex with S-adenosyl-L-methionine and in ternary complex with DNA and S-adenosyl-L- homocysteine. The structures of Hhal methyltransfrase demonstrate a remarkable novel solution to the difficult problem of reaching a target base buried in the double helix: rotation of a DNA nucleotide out of' -the double helix and into the protein binding pocket ('base flipping'). This base flipping mechanism is not unique to DNA methyltransferases, but appears to be widely used in other DNA modification processes such as DNA repair and DNA ligation. The structures also reveal other common properties of the family of DNA methyltransferases: nearly complete separation of sequence recognition and catalysis into two structural domains and nearly identical structure of the sequence-recognition loops despite complete divergence of DNA substrate sequence. Our immediate goals are to dissect the mechanism of base flipping and the catalysis of C5-cytosine methylation by structural studies with mismatched bases, cytosine analogs, or mutant M.Hhal proteins defective at some point in the reaction pathway, and to demonstrate more examples of base flipping and to study the catalytic mechanism of DNA amino-methyltransferases by determining the structures of Pvull N4-cytosine methyltransferase and T4 Dam (DNA adenine methyltransferase) in complex with DNA.
| Ren, Ren; Horton, John R; Zhang, Xing et al. (2018) Detecting and interpreting DNA methylation marks. Curr Opin Struct Biol 53:88-99 |
| Patel, Anamika; Yang, Peng; Tinkham, Matthew et al. (2018) DNA Conformation Induces Adaptable Binding by Tandem Zinc Finger Proteins. Cell 173:221-233.e12 |
| Hashimoto, Hideharu; Wang, Dongxue; Horton, John R et al. (2017) Structural Basis for the Versatile and Methylation-Dependent Binding of CTCF to DNA. Mol Cell 66:711-720.e3 |
| Patel, Anamika; Zhang, Xing; Blumenthal, Robert M et al. (2017) Structural basis of human PR/SET domain 9 (PRDM9) allele C-specific recognition of its cognate DNA sequence. J Biol Chem 292:15994-16002 |
| Lee, Chen-Cheng; Peng, Shih-Huan; Shen, Li et al. (2017) The Role of N-?-acetyltransferase 10 Protein in DNA Methylation and Genomic Imprinting. Mol Cell 68:89-103.e7 |
| Yang, Peng; Wang, Yixuan; Hoang, Don et al. (2017) A placental growth factor is silenced in mouse embryos by the zinc finger protein ZFP568. Science 356:757-759 |
| Estève, Pierre-Olivier; Zhang, Guoqiang; Ponnaluri, V K Chaithanya et al. (2016) Binding of 14-3-3 reader proteins to phosphorylated DNMT1 facilitates aberrant DNA methylation and gene expression. Nucleic Acids Res 44:1642-56 |
| Patel, A; Hashimoto, H; Zhang, X et al. (2016) Characterization of How DNA Modifications Affect DNA Binding by C2H2 Zinc Finger Proteins. Methods Enzymol 573:387-401 |
| Patel, Anamika; Horton, John R; Wilson, Geoffrey G et al. (2016) Structural basis for human PRDM9 action at recombination hot spots. Genes Dev 30:257-65 |
| Zeng, Yaxue; Yao, Bing; Shin, Jaehoon et al. (2016) Lin28A Binds Active Promoters and Recruits Tet1 to Regulate Gene Expression. Mol Cell 61:153-60 |
Showing the most recent 10 out of 103 publications
