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Structure and Function of DNA Methyltransferase 1

Willie Miller-Little & Austin Griffin 


I. Introduction

  DNA methylation is important for the epigenetic regulation of genes, through silencing.  Maintenance of such methylation, in mammals, is primarily mediated by DNA methyltransferase1-(DNMT1).  DNMT1 is a 1620 residue protein composed of a CXXC domain ,two Bromo-adjacent-homology (BAH) domains, and a DNA containing methyltransferase domain, which also contains a Target recognition domain (TRD).   The crystal structures of both the mouse and the Human DNMT1 protein have been solved.  These two proteins share 85% sequence identity and share very similar structures.  This protein functions by the CXXC domain binding specifically to hemimethylated CpG nucleotides, and interacts in such a way that the CXXC-BAH1 linker  between DNA and the protein’s active site, preventing de novo methylation.  It also performs an autoinhibitory mechanism in which unmethylated CpG sites are occluded from the active site, selecting for Hemimethylated CpG dinucleotides.

II. CXXC Domain

The CXXC domain (residues 650-699) contains a crescent like fold.  This single domain makes all sequence specific interactions with the DNA. These interactions target both the major and the minor groove, and contain a 4Bp footprint.  The Major groove interactions are made between the Arg684 Ser685 Lys686 Gln687 which form a loop segment that penetrates the major groove,
making hydrogen bonds.   Lys686 and Gln687 contact the Guanine bases via hydrogen bonds in the unmethylated dinucleotide Ser685 Lys686 interact with the cytosine bases.  However, these are not the only interactions made with the DNA,  the CXXC domain also contains recognition sites of salt bridges from arginines to the phosphodiester backbone of the DNA .  The CXXC domain also aids in the control of not interacting with Methylated CpG sites.  This control occurs due to steric hindrance.  If a methyl group were present on the CpG dinucleotide, it would unfavorably interact with (Arg684 Ser685 Lys686 ) due to steric interference with nearby peptide atoms .  

III. BAH Domains

The BAH1 and BAH2 domains adopt a common fold similar to the Orc1p BAH domain.  These domains are connected by an alpha helix (BAH linker) and form a dumbbell like configuration   , and are both physically associated with the methyltransferase domain.  The BAH1 domain is anchored to the linker alpha helix by a Cys3His-coordinated Zn2+ ion, while the BAH2 domain loop is anchored to the TRD of the methyltransferase domain .

IV. Methyl Transferase

 The Methylt transferase domain in DMNT1 is the main catalytic domain of the protein.  It contains two subdomains, the Target recognition domain (TRD), and the catalytic core, which are separated by a large cleft in the protein, which is occupied by the DNA.  The catalytic core is composed of seven mixed β-sheets   . flanked on either side by three A-helices .  

The DNA in mDNMT1 complex is anchored by the CXXC domain, withdrawn from the DNMT1 active site.  Unmethylated DNA is occluded from the active site because f the autoinhibitory function of the CXXC-BAH1 linker (highlight and zoom, rotate).  The CXXC-BAH1 linker contains a highly acidic segment spanning residues D703-D711 [Figure 3D.] and is positioned between the DNA and the active site .  The BAH2-TRD loop also anchors the TRD in a retracted position, preventing major groove interactions with the DNA.  These two activities function to prevent unmethylated Cpg dinucleotides from entering the active site, and only allows hemimethylated dinucleotides to enter the active site.

V. References

1. J.A. Law, S.E. Jacobsen, Nat. Rev. Genet. 11, 204 (2010).
2. X. Cheng, R.M. Blumenthal, Structure 16, 341 (2008).
3. M. G. Goll, T.H. Bestor, Annu. Rev. Biochem. 74, 481 (2005).
4.  Song J. et. al. Structure of DNMT1-DNA Complex Reveals a Role for Autoinhibition in Maintenance DNA Methylation. Science
vol. 331. (25, February, 2011 )
Watson, James D. Molecular Biology of the Gene 3d Ed.with Keith Roberts. 6th ed. Menlo Park,Calif: W.A.Benjamin, 1976.

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