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- EMDB-42636: Cryo-EM structure of DNMT3A1 UDR in complex with H2AK119Ub-nucleosome -

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Entry
Database: EMDB / ID: EMD-42636
TitleCryo-EM structure of DNMT3A1 UDR in complex with H2AK119Ub-nucleosome
Map dataCryo-EM structure of the DNMT3A1 UDR bound to a H2AK119Ub nucleosome
Sample
  • Complex: DNMT3A1 UDR in complex with H2AK119Ub-nucleosome
    • Protein or peptide: Histone H3.2
    • Protein or peptide: Histone H4
    • Protein or peptide: Histone H2A
    • Protein or peptide: Histone H2B 1.1
    • Protein or peptide: DNA (cytosine-5)-methyltransferase 3A
    • DNA: DNA (146-MER)
    • DNA: DNA (146-MER)
KeywordsDNMT3A1 / Chromatin / H2A lysine 119 monoubiquitination / DNA Methyltransferase / GENE REGULATION
Function / homology
Function and homology information


positive regulation of cellular response to hypoxia / transposable element silencing by piRNA-mediated DNA methylation / protein-cysteine methyltransferase activity / regulatory ncRNA-mediated heterochromatin formation / DNA (cytosine-5-)-methyltransferase activity / cellular response to bisphenol A / DNA (cytosine-5-)-methyltransferase activity, acting on CpN substrates / DNA (cytosine-5-)-methyltransferase activity, acting on CpNpG substrates / unmethylated CpG binding / DNA (cytosine-5-)-methyltransferase ...positive regulation of cellular response to hypoxia / transposable element silencing by piRNA-mediated DNA methylation / protein-cysteine methyltransferase activity / regulatory ncRNA-mediated heterochromatin formation / DNA (cytosine-5-)-methyltransferase activity / cellular response to bisphenol A / DNA (cytosine-5-)-methyltransferase activity, acting on CpN substrates / DNA (cytosine-5-)-methyltransferase activity, acting on CpNpG substrates / unmethylated CpG binding / DNA (cytosine-5-)-methyltransferase / autosome genomic imprinting / SUMOylation of DNA methylation proteins / XY body / cellular response to ethanol / response to vitamin A / response to ionizing radiation / DNA methylation-dependent constitutive heterochromatin formation / negative regulation of gene expression via chromosomal CpG island methylation / lncRNA binding / hepatocyte apoptotic process / chromosome, centromeric region / catalytic complex / heterochromatin / DNA methylation / Transferases; Transferring one-carbon groups; Methyltransferases / PRC2 methylates histones and DNA / post-embryonic development / Defective pyroptosis / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / cellular response to amino acid stimulus / response to cocaine / response to lead ion / euchromatin / RMTs methylate histone arginines / nuclear matrix / response to toxic substance / neuron differentiation / transcription corepressor activity / structural constituent of chromatin / nucleosome / heterochromatin formation / nucleosome assembly / response to estradiol / spermatogenesis / methylation / cellular response to hypoxia / RNA polymerase II-specific DNA-binding transcription factor binding / RNA polymerase II cis-regulatory region sequence-specific DNA binding / protein heterodimerization activity / response to xenobiotic stimulus / negative regulation of DNA-templated transcription / chromatin binding / negative regulation of transcription by RNA polymerase II / DNA binding / zinc ion binding / nucleoplasm / identical protein binding / nucleus / cytoplasm
Similarity search - Function
DNA (cytosine-5)-methyltransferase 3A, ADD domain / : / DNA (cytosine-5-)-methyltransferase, N-terminal / DNMT3, cysteine rich ADD domain / : / DNMT3, cysteine rich ADD domain, GATA1-like zinc finger / DNMT3, ADD PHD zinc finger / ADD domain / ADD domain profile. / DNA methylase, C-5 cytosine-specific, active site ...DNA (cytosine-5)-methyltransferase 3A, ADD domain / : / DNA (cytosine-5-)-methyltransferase, N-terminal / DNMT3, cysteine rich ADD domain / : / DNMT3, cysteine rich ADD domain, GATA1-like zinc finger / DNMT3, ADD PHD zinc finger / ADD domain / ADD domain profile. / DNA methylase, C-5 cytosine-specific, active site / C-5 cytosine-specific DNA methylases active site. / C-5 cytosine-specific DNA methylase (Dnmt) domain profile. / C-5 cytosine methyltransferase / C-5 cytosine-specific DNA methylase / domain with conserved PWWP motif / PWWP domain / PWWP domain profile. / PWWP domain / : / Histone H2B signature. / Histone H2B / Histone H2B / Histone H2A conserved site / Histone H2A signature. / Histone H2A, C-terminal domain / C-terminus of histone H2A / Histone H2A / Histone 2A / TATA box binding protein associated factor / TATA box binding protein associated factor (TAF), histone-like fold domain / Histone H4, conserved site / Histone H4 signature. / Histone H4 / Histone H4 / CENP-T/Histone H4, histone fold / Centromere kinetochore component CENP-T histone fold / Histone H3 signature 1. / Histone H3 signature 2. / Histone H3 / Histone H3/CENP-A / Histone H2A/H2B/H3 / Core histone H2A/H2B/H3/H4 / Histone-fold / S-adenosyl-L-methionine-dependent methyltransferase superfamily
Similarity search - Domain/homology
Histone H4 / Histone H2B 1.1 / Histone H3.2 / Histone H2A / DNA (cytosine-5)-methyltransferase 3A
Similarity search - Component
Biological speciesXenopus laevis (African clawed frog) / Homo sapiens (human) / Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.88 Å
AuthorsGretarsson K / Abini-Agbomson S / Armache K-J / Lu C
Funding support United States, 4 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM115882 United States
The Mark Foundation United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)5T32GM088118 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA266978 United States
CitationJournal: Sci Adv / Year: 2024
Title: Cancer-associated DNA hypermethylation of Polycomb targets requires DNMT3A dual recognition of histone H2AK119 ubiquitination and the nucleosome acidic patch.
Authors: Kristjan H Gretarsson / Stephen Abini-Agbomson / Susan L Gloor / Daniel N Weinberg / Jamie L McCuiston / Vishnu Udayakumar Sunitha Kumary / Allison R Hickman / Varun Sahu / Rachel Lee / ...Authors: Kristjan H Gretarsson / Stephen Abini-Agbomson / Susan L Gloor / Daniel N Weinberg / Jamie L McCuiston / Vishnu Udayakumar Sunitha Kumary / Allison R Hickman / Varun Sahu / Rachel Lee / Xinjing Xu / Natalie Lipieta / Samuel Flashner / Oluwatobi A Adeleke / Irina K Popova / Hailey F Taylor / Kelsey Noll / Carolina Lin Windham / Danielle N Maryanski / Bryan J Venters / Hiroshi Nakagawa / Michael-Christopher Keogh / Karim-Jean Armache / Chao Lu /
Abstract: During tumor development, promoter CpG islands that are normally silenced by Polycomb repressive complexes (PRCs) become DNA-hypermethylated. The molecular mechanism by which de novo DNA ...During tumor development, promoter CpG islands that are normally silenced by Polycomb repressive complexes (PRCs) become DNA-hypermethylated. The molecular mechanism by which de novo DNA methyltransferase(s) [DNMT(s)] catalyze CpG methylation at PRC-regulated regions remains unclear. Here, we report a cryo-electron microscopy structure of the DNMT3A long isoform (DNMT3A1) amino-terminal region in complex with a nucleosome carrying PRC1-mediated histone H2A lysine-119 monoubiquitination (H2AK119Ub). We identify regions within the DNMT3A1 amino terminus that bind H2AK119Ub and the nucleosome acidic patch. This bidentate interaction is required for effective DNMT3A1 engagement with H2AK119Ub-modified chromatin in cells. Further, aberrant redistribution of DNMT3A1 to Polycomb target genes recapitulates the cancer-associated DNA hypermethylation signature and inhibits their transcriptional activation during cell differentiation. This effect is rescued by disruption of the DNMT3A1-acidic patch interaction. Together, our analyses reveal a binding interface critical for mediating promoter CpG island DNA hypermethylation, a major molecular hallmark of cancer.
History
DepositionNov 5, 2023-
Header (metadata) releaseSep 11, 2024-
Map releaseSep 11, 2024-
UpdateMay 21, 2025-
Current statusMay 21, 2025Processing site: RCSB / Status: Released

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Structure visualization

Downloads & links

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Map

FileDownload / File: emd_42636.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM structure of the DNMT3A1 UDR bound to a H2AK119Ub nucleosome
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 320 pix.
= 272. Å		0.85 Å/pix.
x 320 pix.
= 272. Å		0.85 Å/pix.
x 320 pix.
= 272. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.85 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0946
Minimum - Maximum0.0 - 0.70772785
Average (Standard dev.)0.0052230153 (±0.021674925)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 272.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : DNMT3A1 UDR in complex with H2AK119Ub-nucleosome

EntireName: DNMT3A1 UDR in complex with H2AK119Ub-nucleosome
Components
  • Complex: DNMT3A1 UDR in complex with H2AK119Ub-nucleosome
    • Protein or peptide: Histone H3.2
    • Protein or peptide: Histone H4
    • Protein or peptide: Histone H2A
    • Protein or peptide: Histone H2B 1.1
    • Protein or peptide: DNA (cytosine-5)-methyltransferase 3A
    • DNA: DNA (146-MER)
    • DNA: DNA (146-MER)

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Supramolecule #1: DNMT3A1 UDR in complex with H2AK119Ub-nucleosome

SupramoleculeName: DNMT3A1 UDR in complex with H2AK119Ub-nucleosome / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Xenopus laevis (African clawed frog)

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Macromolecule #1: Histone H3.2

MacromoleculeName: Histone H3.2 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Xenopus laevis (African clawed frog)
Molecular weightTheoretical: 15.421101 KDa
Recombinant expressionOrganism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
SequenceString:
MARTKQTARK STGGKAPRKQ LATKAARKSA PATGGVKKPH RYRPGTVALR EIRRYQKSTE LLIRKLPFQR LVREIAQDFK TDLRFQSSA VMALQEASEA YLVGLFEDTN LCAIHAKRVT IMPKDIQLAR RIRGERA

UniProtKB: Histone H3.2

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Macromolecule #2: Histone H4

MacromoleculeName: Histone H4 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Xenopus laevis (African clawed frog)
Molecular weightTheoretical: 11.394426 KDa
Recombinant expressionOrganism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
SequenceString:
MSGRGKGGKG LGKGGAKRHR KVLRDNIQGI TKPAIRRLAR RGGVKRISGL IYEETRGVLK VFLENVIRDA VTYTEHAKRK TVTAMDVVY ALKRQGRTLY GFGG

UniProtKB: Histone H4

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Macromolecule #3: Histone H2A

MacromoleculeName: Histone H2A / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Xenopus laevis (African clawed frog)
Molecular weightTheoretical: 14.109436 KDa
Recombinant expressionOrganism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
SequenceString:
MSGRGKQGGK TRAKAKTRSS RAGLQFPVGR VHRLLRKGNY AERVGAGAPV YLAAVLEYLT AEILELAGNA ARDNKKTRII PRHLQLAVR NDEELNKLLG RVTIAQGGVL PNIQSVLLPK KTESSKSAKS K

UniProtKB: Histone H2A

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Macromolecule #4: Histone H2B 1.1

MacromoleculeName: Histone H2B 1.1 / type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Xenopus laevis (African clawed frog)
Molecular weightTheoretical: 13.979291 KDa
Recombinant expressionOrganism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
SequenceString:
MPEPAKSAPA PKKGSKKAVT KTQKKDGKKR RKTRKESYAI YVYKVLKQVH PDTGISSKAM SIMNSFVNDV FERIAGEASR LAHYNKRST ITSREIQTAV RLLLPGELAK HAVSEGTKAV TKYTSAK

UniProtKB: Histone H2B 1.1

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Macromolecule #5: DNA (cytosine-5)-methyltransferase 3A

MacromoleculeName: DNA (cytosine-5)-methyltransferase 3A / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO / EC number: DNA (cytosine-5-)-methyltransferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 9.028392 KDa
SequenceString:
HHHHHHESMK MEGSRGRLRG GLGWESSLRQ RPMPRLTFQA GDPYYISKRK RDEWLARWKR EAEKKAKVIA GMNAVE

UniProtKB: DNA (cytosine-5)-methyltransferase 3A

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Macromolecule #6: DNA (146-MER)

MacromoleculeName: DNA (146-MER) / type: dna / ID: 6 / Number of copies: 1 / Classification: DNA
Source (natural)Organism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
Molecular weightTheoretical: 44.82457 KDa
SequenceString: (DT)(DC)(DG)(DA)(DG)(DA)(DA)(DT)(DC)(DC) (DC)(DG)(DG)(DT)(DG)(DC)(DC)(DG)(DA)(DG) (DG)(DC)(DC)(DG)(DC)(DT)(DC)(DA)(DA) (DT)(DT)(DG)(DG)(DT)(DC)(DG)(DT)(DA)(DG) (DA) (DC)(DA)(DG)(DC)(DT)(DC) ...String:
(DT)(DC)(DG)(DA)(DG)(DA)(DA)(DT)(DC)(DC) (DC)(DG)(DG)(DT)(DG)(DC)(DC)(DG)(DA)(DG) (DG)(DC)(DC)(DG)(DC)(DT)(DC)(DA)(DA) (DT)(DT)(DG)(DG)(DT)(DC)(DG)(DT)(DA)(DG) (DA) (DC)(DA)(DG)(DC)(DT)(DC)(DT)(DA) (DG)(DC)(DA)(DC)(DC)(DG)(DC)(DT)(DT)(DA) (DA)(DA) (DC)(DG)(DC)(DA)(DC)(DG)(DT) (DA)(DC)(DG)(DG)(DA)(DT)(DT)(DC)(DT)(DC) (DC)(DC)(DC) (DC)(DG)(DC)(DG)(DT)(DT) (DT)(DT)(DA)(DA)(DC)(DC)(DG)(DC)(DC)(DA) (DA)(DG)(DG)(DG) (DG)(DA)(DT)(DT)(DA) (DC)(DT)(DC)(DC)(DC)(DT)(DA)(DG)(DT)(DC) (DT)(DC)(DC)(DA)(DG) (DG)(DC)(DA)(DC) (DG)(DT)(DG)(DT)(DC)(DA)(DG)(DA)(DT)(DA) (DT)(DA)(DT)(DA)(DC)(DA) (DT)(DC)(DC) (DG)(DA)(DT)

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Macromolecule #7: DNA (146-MER)

MacromoleculeName: DNA (146-MER) / type: dna / ID: 7 / Number of copies: 1 / Classification: DNA
Source (natural)Organism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
Molecular weightTheoretical: 45.304863 KDa
SequenceString: (DA)(DT)(DC)(DG)(DG)(DA)(DT)(DG)(DT)(DA) (DT)(DA)(DT)(DA)(DT)(DC)(DT)(DG)(DA)(DC) (DA)(DC)(DG)(DT)(DG)(DC)(DC)(DT)(DG) (DG)(DA)(DG)(DA)(DC)(DT)(DA)(DG)(DG)(DG) (DA) (DG)(DT)(DA)(DA)(DT)(DC) ...String:
(DA)(DT)(DC)(DG)(DG)(DA)(DT)(DG)(DT)(DA) (DT)(DA)(DT)(DA)(DT)(DC)(DT)(DG)(DA)(DC) (DA)(DC)(DG)(DT)(DG)(DC)(DC)(DT)(DG) (DG)(DA)(DG)(DA)(DC)(DT)(DA)(DG)(DG)(DG) (DA) (DG)(DT)(DA)(DA)(DT)(DC)(DC)(DC) (DC)(DT)(DT)(DG)(DG)(DC)(DG)(DG)(DT)(DT) (DA)(DA) (DA)(DA)(DC)(DG)(DC)(DG)(DG) (DG)(DG)(DG)(DA)(DG)(DA)(DA)(DT)(DC)(DC) (DG)(DT)(DA) (DC)(DG)(DT)(DG)(DC)(DG) (DT)(DT)(DT)(DA)(DA)(DG)(DC)(DG)(DG)(DT) (DG)(DC)(DT)(DA) (DG)(DA)(DG)(DC)(DT) (DG)(DT)(DC)(DT)(DA)(DC)(DG)(DA)(DC)(DC) (DA)(DA)(DT)(DT)(DG) (DA)(DG)(DC)(DG) (DG)(DC)(DC)(DT)(DC)(DG)(DG)(DC)(DA)(DC) (DC)(DG)(DG)(DG)(DA)(DT) (DT)(DC)(DT) (DC)(DG)(DA)

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.3 mg/mL
BufferpH: 7.9
Component:
ConcentrationFormulaName
50.0 mMNaClSodium chloride
50.0 mMC8H18N2O4SHEPES
2.0 mMC4H10O2S2DTT

Details: 50 mM HEPES pH 7.9, 100 mM NaCl, 2 mM DTT
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.3 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 2896025
CTF correctionType: NONE
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.88 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 55652
Initial angle assignmentType: OTHER
Final angle assignmentType: MAXIMUM LIKELIHOOD

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