The cell cycle-regulated DNA adenine methyltransferase CcrM opens a bubble at its DNA recognition site

Horton, John R.; Woodcock, Clayton B.; Opot, Sifa B.; Reich, Norbert O.; Zhang, Xing; Cheng, Xiaodong

doi:10.1038/s41467-019-12498-7

The cell cycle-regulated DNA adenine methyltransferase CcrM opens a bubble at its DNA recognition site

Journal Article · Thu Oct 10 00:00:00 EDT 2019 · Nature Communications

DOI:https://doi.org/10.1038/s41467-019-12498-7· OSTI ID:1575008

^[1]; Woodcock, Clayton B. ^[1]; Opot, Sifa B. ^[1]; Reich, Norbert O. ^[2]; Zhang, Xing ^[1]; ^[1]

Univ. of Texas MD Anderson Cancer Center, Houston, TX (United States)
Univ. of California, Santa Barbara, CA (United States)

The Caulobacter crescentus cell cycle-regulated DNA methyltransferase (CcrM) methylates the adenine of hemimethylated GANTC after replication. Here we present the structure of CcrM in complex with double-stranded DNA containing the recognition sequence. CcrM contains an N-terminal methyltransferase domain and a C-terminal nonspecific DNA-binding domain. CcrM is a dimer, with each monomer contacting primarily one DNA strand: the methyltransferase domain of one molecule binds the target strand, recognizes the target sequence, and catalyzes methyl transfer, while the C-terminal domain of the second molecule binds the non-target strand. The DNA contacts at the 5-base pair recognition site results in dramatic DNA distortions including bending, unwinding and base flipping. The two DNA strands are pulled apart, creating a bubble comprising four recognized base pairs. The five bases of the target strand are recognized meticulously by stacking contacts, van der Waals interactions and specific Watson–Crick polar hydrogen bonds to ensure high enzymatic specificity.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: Cancer Prevention and Research Inst. of Texas (CPRIT); National Institutes of Health (NIH); USDOE

OSTI ID:: 1575008

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 10; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

References (61)

A Caulobacter DNA Methyltransferase that Functions only in the Predivisional Cell Zweiger, Gary; Marczynski, Gregory; Shapiro, Lucille Journal of Molecular Biology, Vol. 235, Issue 2 https://doi.org/10.1006/jmbi.1994.1007	journal	January 1994
Structure-guided Analysis Reveals Nine Sequence Motifs Conserved among DNA Amino-methyl-transferases, and Suggests a Catalytic Mechanism for these Enzymes Malone, Thomas; Blumenthal, Robert M.; Cheng, Xiaodong Journal of Molecular Biology, Vol. 253, Issue 4 https://doi.org/10.1006/jmbi.1995.0577	journal	November 1995
A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei Leonhardt, Heinrich; Page, Andrea W.; Weier, Heinz-Ulrich Cell, Vol. 71, Issue 5 https://doi.org/10.1016/0092-8674(92)90561-p	journal	November 1992
Targeted mutation of the DNA methyltransferase gene results in embryonic lethality Li, En; Bestor, Timothy H.; Jaenisch, Rudolf Cell, Vol. 69, Issue 6 https://doi.org/10.1016/0092-8674(92)90611-f	journal	June 1992
Hhal methyltransferase flips its target base out of the DNA helix Klimasauskas, Saulius; Kumar, Sanjay; Roberts, Richard J. Cell, Vol. 76, Issue 2 https://doi.org/10.1016/0092-8674(94)90342-5	journal	January 1994
Atomic model of a pyrimidine dimer excision repair enzyme complexed with a dna substrate: Structural basis for damaged DNA recognition Vassylyev, Dmitry G.; Kashiwagi, Tatsuki; Mikami, Yuriko Cell, Vol. 83, Issue 5 https://doi.org/10.1016/0092-8674(95)90190-6	journal	December 1995
Investigation of the C-terminal domain of the bacterial DNA-(adenine N6)-methyltransferase CcrM Maier, Johannes A. H.; Albu, Razvan F.; Jurkowski, Tomasz P. Biochimie, Vol. 119 https://doi.org/10.1016/j.biochi.2015.10.011	journal	December 2015
Transition from Nonspecific to Specific DNA Interactions along the Substrate-Recognition Pathway of Dam Methyltransferase Horton, John R.; Liebert, Kirsten; Hattman, Stanley Cell, Vol. 121, Issue 3 https://doi.org/10.1016/j.cell.2005.02.021	journal	May 2005
Helix Unwinding and Base Flipping Enable Human MTERF1 to Terminate Mitochondrial Transcription Yakubovskaya, Elena; Mejia, Edison; Byrnes, James Cell, Vol. 141, Issue 6 https://doi.org/10.1016/j.cell.2010.05.018	journal	June 2010
Timing and targeting: The biological functions of Dam methylation in E. coli Messer, Walter; Noyer-Weidner, Mario Cell, Vol. 54, Issue 6 https://doi.org/10.1016/s0092-8674(88)90911-7	journal	September 1988
Surprising similarities in structure comparison Gibrat, Jean-Francois; Madej, Thomas; Bryant, Stephen H. Current Opinion in Structural Biology, Vol. 6, Issue 3 https://doi.org/10.1016/s0959-440x(96)80058-3	journal	June 1996
Many paths to methyltransfer: a chronicle of convergence Schubert, Heidi L.; Blumenthal, Robert M.; Cheng, Xiaodong Trends in Biochemical Sciences, Vol. 28, Issue 6 https://doi.org/10.1016/s0968-0004(03)00090-2	journal	June 2003
Caulobacter crescentus Cell Cycle-Regulated DNA Methyltransferase Uses a Novel Mechanism for Substrate Recognition Woodcock, Clayton B.; Yakubov, Aziz B.; Reich, Norbert O. Biochemistry, Vol. 56, Issue 30 https://doi.org/10.1021/acs.biochem.7b00378	journal	July 2017
Structural basis of asymmetric DNA methylation and ATP-triggered long-range diffusion by EcoP15I Gupta, Yogesh K.; Chan, Siu-Hong; Xu, Shuang-yong Nature Communications, Vol. 6, Issue 1 https://doi.org/10.1038/ncomms8363	journal	June 2015
The Phyre2 web portal for protein modeling, prediction and analysis Kelley, Lawrence A.; Mezulis, Stefans; Yates, Christopher M. Nature Protocols, Vol. 10, Issue 6 https://doi.org/10.1038/nprot.2015.053	journal	May 2015
The PWWP domain of mammalian DNA methyltransferase Dnmt3b defines a new family of DNA-binding folds Qiu, Chen; Sawada, Ken; Zhang, Xing Nature Structural Biology https://doi.org/10.1038/nsb759	journal	February 2002
Structure of the bacteriophage T4 DNA adenine methyltransferase Yang, Zhe; Horton, John R.; Zhou, Lan Nature Structural & Molecular Biology, Vol. 10, Issue 10 https://doi.org/10.1038/nsb973	journal	August 2003
Global methylation state at base-pair resolution of the Caulobacter genome throughout the cell cycle Kozdon, J. B.; Melfi, M. D.; Luong, K. Proceedings of the National Academy of Sciences, Vol. 110, Issue 48 https://doi.org/10.1073/pnas.1319315110	journal	November 2013
DNA methyltransferases and epigenetic regulation in bacteria Adhikari, Satish; Curtis, Patrick D. FEMS Microbiology Reviews, Vol. 40, Issue 5 https://doi.org/10.1093/femsre/fuw023	journal	July 2016
Structure of pvu II DNA-(cytosine N4) methyltransferase, an example of domain permutation and protein fold assignment Gong, W. Nucleic Acids Research, Vol. 25, Issue 14 https://doi.org/10.1093/nar/25.14.2702	journal	July 1997
Amino acid-base interactions: a three-dimensional analysis of protein-DNA interactions at an atomic level Luscombe, N. M. Nucleic Acids Research, Vol. 29, Issue 13 https://doi.org/10.1093/nar/29.13.2860	journal	July 2001
Structures of Escherichia coli DNA adenine methyltransferase (Dam) in complex with a non-GATC sequence: potential implications for methylation-independent transcriptional repression Horton, John R.; Zhang, Xing; Blumenthal, Robert M. Nucleic Acids Research, Vol. 43, Issue 8 https://doi.org/10.1093/nar/gkv251	journal	April 2015
Structural basis for human PRDM9 action at recombination hot spots Patel, Anamika; Horton, John R.; Wilson, Geoffrey G. Genes & Development, Vol. 30, Issue 3 https://doi.org/10.1101/gad.274928.115	journal	February 2016
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/s0021889807021206	journal	July 2007
Coot model-building tools for molecular graphics Emsley, Paul; Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132 https://doi.org/10.1107/s0907444904019158	journal	November 2004
Towards automated crystallographic structure refinement with phenix.refine Afonine, Pavel V.; Grosse-Kunstleve, Ralf W.; Echols, Nathaniel Acta Crystallographica Section D Biological Crystallography, Vol. 68, Issue 4 https://doi.org/10.1107/s0907444912001308	journal	March 2012
Base Flipping Roberts, Richard J.; Cheng, Xiaodong Annual Review of Biochemistry, Vol. 67, Issue 1 https://doi.org/10.1146/annurev.biochem.67.1.181	journal	June 1998
Biochemical and structural characterization of a DNA N6-adenine methyltransferase from Helicobacter pylori Ma, Bo; Ma, Ji; Liu, Dong Oncotarget, Vol. 7, Issue 27 https://doi.org/10.18632/oncotarget.9692	journal	May 2016
DNA Interaction of the CcrM DNA Methyltransferase: A Mutational and Modeling Study Albu, Razvan F.; Zacharias, Martin; Jurkowski, Tomasz P. ChemBioChem, Vol. 13, Issue 9 https://doi.org/10.1002/cbic.201200082	journal	May 2012
Cloning and sequencing of a cDNA encoding DNA methyltransferase of mouse cells Bestor, Timothy; Laudano, Andrew; Mattaliano, Robert Journal of Molecular Biology, Vol. 203, Issue 4 https://doi.org/10.1016/0022-2836(88)90122-2	journal	October 1988
A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei Leonhardt, Heinrich; Page, Andrea W.; Weier, Heinz-Ulrich Cell, Vol. 71, Issue 5 https://doi.org/10.1016/0092-8674(92)90561-P	journal	November 1992
Targeted mutation of the DNA methyltransferase gene results in embryonic lethality Li, En; Bestor, Timothy H.; Jaenisch, Rudolf Cell, Vol. 69, Issue 6 https://doi.org/10.1016/0092-8674(92)90611-F	journal	June 1992
Timing and targeting: The biological functions of Dam methylation in E. coli Messer, Walter; Noyer-Weidner, Mario Cell, Vol. 54, Issue 6 https://doi.org/10.1016/S0092-8674(88)90911-7	journal	September 1988
Surprising similarities in structure comparison Gibrat, Jean-Francois; Madej, Thomas; Bryant, Stephen H. Current Opinion in Structural Biology, Vol. 6, Issue 3 https://doi.org/10.1016/S0959-440X(96)80058-3	journal	June 1996
Many paths to methyltransfer: a chronicle of convergence Schubert, Heidi L.; Blumenthal, Robert M.; Cheng, Xiaodong Trends in Biochemical Sciences, Vol. 28, Issue 6 https://doi.org/10.1016/S0968-0004(03)00090-2	journal	June 2003
N-methyladenine DNA Modification in Glioblastoma Xie, Qi; Wu, Tao P.; Gimple, Ryan C. Cell, Vol. 175, Issue 5 https://doi.org/10.1016/j.cell.2018.10.006	journal	November 2018
Identification of a DNA N6-Adenine Methyltransferase Complex and Its Impact on Chromatin Organization Beh, Leslie Y.; Debelouchina, Galia T.; Clay, Derek M. Cell, Vol. 177, Issue 7 https://doi.org/10.1016/j.cell.2019.04.028	journal	June 2019
Permanganate/S1 Nuclease Footprinting Reveals Non-B DNA Structures with Regulatory Potential across a Mammalian Genome Kouzine, Fedor; Wojtowicz, Damian; Baranello, Laura Cell Systems, Vol. 4, Issue 3 https://doi.org/10.1016/j.cels.2017.01.013	journal	March 2017
Structure and Substrate Recognition of the Escherichia coli DNA Adenine Methyltransferase Horton, John R.; Liebert, Kirsten; Bekes, Miklos Journal of Molecular Biology, Vol. 358, Issue 2 https://doi.org/10.1016/j.jmb.2006.02.028	journal	April 2006
An Adversarial DNA N6-Methyladenine-Sensor Network Preserves Polycomb Silencing Kweon, Soo-Mi; Chen, Yibu; Moon, Eugene Molecular Cell, Vol. 74, Issue 6 https://doi.org/10.1016/j.molcel.2019.03.018	journal	June 2019
The m ⁶ A Writer: Rise of a Machine for Growing Tasks Balacco, Dario L.; Soller, Matthias Biochemistry, Vol. 58, Issue 5 https://doi.org/10.1021/acs.biochem.8b01166	journal	December 2018
RNA m6A methylation regulates the ultraviolet-induced DNA damage response Xiang, Yang; Laurent, Benoit; Hsu, Chih-Hung Nature, Vol. 543, Issue 7646 https://doi.org/10.1038/nature21671	journal	March 2017
Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control Barbieri, Isaia; Tzelepis, Konstantinos; Pandolfini, Luca Nature, Vol. 552, Issue 7683 https://doi.org/10.1038/nature24678	journal	November 2017
A METTL3–METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation Liu, Jianzhao; Yue, Yanan; Han, Dali Nature Chemical Biology, Vol. 10, Issue 2 https://doi.org/10.1038/nchembio.1432	journal	December 2013
N6-methyladenosine mRNA marking promotes selective translation of regulons required for human erythropoiesis Kuppers, Daniel A.; Arora, Sonali; Lim, Yiting Nature Communications, Vol. 10, Issue 1 https://doi.org/10.1038/s41467-019-12518-6	journal	October 2019
Histone H3 trimethylation at lysine 36 guides m6A RNA modification co-transcriptionally Huang, Huilin; Weng, Hengyou; Zhou, Keren Nature, Vol. 567, Issue 7748 https://doi.org/10.1038/s41586-019-1016-7	journal	March 2019
A view of consecutive binding events from structures of tetrameric endonuclease Sfi I bound to DNA : The structure of Vanamee, Éva Scheuring; Viadiu, Hector; Kucera, Rebecca The EMBO Journal, Vol. 24, Issue 23 https://doi.org/10.1038/sj.emboj.7600880	journal	November 2005
A cell cycle-regulated adenine DNA methyltransferase from Caulobacter crescentus processively methylates GANTC sites on hemimethylated DNA Berdis, A. J.; Lee, I.; Coward, J. K. Proceedings of the National Academy of Sciences, Vol. 95, Issue 6 https://doi.org/10.1073/pnas.95.6.2874	journal	March 1998
Identification of the Active Oligomeric State of an Essential Adenine DNA Methyltransferase from Caulobacter crescentus Shier, Vincent K.; Hancey, Carey J.; Benkovic, Stephen J. Journal of Biological Chemistry, Vol. 276, Issue 18 https://doi.org/10.1074/jbc.M010688200	journal	February 2001
Structures of Liganded and Unliganded Rsr I N 6-Adenine DNA Methyltransferase : A DISTINCT ORIENTATION FOR ACTIVE COFACTOR BINDING Thomas, Chad B.; Scavetta, Robert D.; Gumport, Richard I. Journal of Biological Chemistry, Vol. 278, Issue 28 https://doi.org/10.1074/jbc.M303751200	journal	May 2003
Carbon-Oxygen Hydrogen Bonding in Biological Structure and Function Horowitz, Scott; Trievel, Raymond C. Journal of Biological Chemistry, Vol. 287, Issue 50 https://doi.org/10.1074/jbc.R112.418574	journal	October 2012
The highly specific, cell cycle–regulated methyltransferase from Caulobacter crescentus relies on a novel DNA recognition mechanism Reich, Norbert O.; Dang, Eric; Kurnik, Martin Journal of Biological Chemistry, Vol. 293, Issue 49 https://doi.org/10.1074/jbc.RA118.005212	journal	October 2018
Crystal structure of MboIIA methyltransferase Osipiuk, J. Nucleic Acids Research, Vol. 31, Issue 18 https://doi.org/10.1093/nar/gkg713	journal	September 2003
The non-specific adenine DNA methyltransferase M.EcoGII Murray, Iain A.; Morgan, Richard D.; Luyten, Yvette Nucleic Acids Research, Vol. 46, Issue 2 https://doi.org/10.1093/nar/gkx1191	journal	December 2017
Stress-Induced DNA Duplex Destabilization (SIDD) in the E. coli Genome: SIDD Sites Are Closely Associated With Promoters Wang, H. Genome Research, Vol. 14, Issue 8 https://doi.org/10.1101/gr.2080004	journal	August 2004
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
Multiparametric scaling of diffraction intensities Otwinowski, Zbyszek; Borek, Dominika; Majewski, Wladyslaw Acta Crystallographica Section A Foundations of Crystallography, Vol. 59, Issue 3 https://doi.org/10.1107/S0108767303005488	journal	April 2003
Coot model-building tools for molecular graphics Emsley, Paul; Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132 https://doi.org/10.1107/S0907444904019158	journal	November 2004
Towards automated crystallographic structure refinement with phenix.refine Afonine, Pavel V.; Grosse-Kunstleve, Ralf W.; Echols, Nathaniel Acta Crystallographica Section D Biological Crystallography, Vol. 68, Issue 4 https://doi.org/10.1107/S0907444912001308	journal	March 2012
Structure and Function of DNA Methyltransferases Cheng, X. Annual Review of Biophysics and Biomolecular Structure, Vol. 24, Issue 1 https://doi.org/10.1146/annurev.bb.24.060195.001453	journal	June 1995
DNA methylation on N6-adenine in mammalian embryonic stem cells Yongquan, Lai,; Kaixuan, Lin,; P., Wu, Tao The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/982a-3f06	text	January 2016

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