Eukaryotic cytosine methylation has been involved in such diverse biological functions as gene repression, Xchromosome inactivation, genome imprinting, and replication timing. DNA cytosine methylation is essential for the normal development of plant and mouse. Moreover, alterations in genome methylation patterns contribute to the genesis of human cancers. Our long-term goal is to understand the two sides of mammalian DNA methylation from a structural standpoint: a class of enzymes called DNA cytosine-5-rnethyltransferases (DNMTs) that methylate DNA and a class of proteins containing a methyl-CpG-binding domain (MBD) that bind to methylated DNA. In this application, his immediate focus is on three mammalian enzymes (Dnmtl, Dnmt2, and Dnmt3b), and five methyl-CpG binding proteins (MeCP2, MBD1 to MBD4). Two human genetic diseases (ICF and Rett syndromes) have been attributed directly to mutations in Dnmt3b and MeCP2.
Our specific aims are: 1. to determine the structure of full-length human Dnmt2; 2. to determine several domain structures of mouse Dnmt3b; 3. to determine several domain structures of human Dnmt1, and 4. to determine the structures from one of five MBD domain-containing proteins and its complex with the methylated CpG-containing 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 |
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