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The N-terminal region of DNMT3A engages the nucleosome surface to aid chromatin recruitment

DNA methyltransferase 3A (DNMT3A) plays a critical role in establishing and maintaining DNA methylation patterns in vertebrates. Here we structurally and biochemically explore the interaction of DNMT3A1 with diverse modified nucleosomes indicative of different chromatin environments. A cryo-EM struc...

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Published in:EMBO reports 2024-11, Vol.25 (12), p.5743-5779
Main Authors: Wapenaar, Hannah, Clifford, Gillian, Rolls, Willow, Pasquier, Moira, Burdett, Hayden, Zhang, Yujie, Deák, Gauri, Zou, Juan, Spanos, Christos, Taylor, Mark R D, Mills, Jacquie, Watson, James A, Kumar, Dhananjay, Clark, Richard, Das, Alakta, Valsakumar, Devisree, Bramham, Janice, Voigt, Philipp, Sproul, Duncan, Wilson, Marcus D
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container_end_page 5779
container_issue 12
container_start_page 5743
container_title EMBO reports
container_volume 25
creator Wapenaar, Hannah
Clifford, Gillian
Rolls, Willow
Pasquier, Moira
Burdett, Hayden
Zhang, Yujie
Deák, Gauri
Zou, Juan
Spanos, Christos
Taylor, Mark R D
Mills, Jacquie
Watson, James A
Kumar, Dhananjay
Clark, Richard
Das, Alakta
Valsakumar, Devisree
Bramham, Janice
Voigt, Philipp
Sproul, Duncan
Wilson, Marcus D
description DNA methyltransferase 3A (DNMT3A) plays a critical role in establishing and maintaining DNA methylation patterns in vertebrates. Here we structurally and biochemically explore the interaction of DNMT3A1 with diverse modified nucleosomes indicative of different chromatin environments. A cryo-EM structure of the full-length DNMT3A1-DNMT3L complex with a H2AK119ub nucleosome reveals that the DNMT3A1 ubiquitin-dependent recruitment (UDR) motif interacts specifically with H2AK119ub and makes extensive contacts with the core nucleosome histone surface. This interaction facilitates robust DNMT3A1 binding to nucleosomes, and previously unexplained DNMT3A disease-associated mutations disrupt this interface. Furthermore, the UDR-nucleosome interaction synergises with other DNMT3A chromatin reading elements in the absence of histone ubiquitylation. H2AK119ub does not stimulate DNMT3A DNA methylation activity, as observed for the previously described H3K36me2 mark, which may explain low levels of DNA methylation on H2AK119ub marked facultative heterochromatin. This study highlights the importance of multivalent binding of DNMT3A to histone modifications and the nucleosome surface and increases our understanding of how DNMT3A1 chromatin recruitment occurs. Synopsis A UDR motif in DNMT3A acts in concert with other chromatin reading regions to promote chromatin recruitment. A cryo-EM structure reveals that DNMT3A1 binds to H2AK119ub-marked nucleosomes through its UDR motif, although this mark does not enhance DNA methylation activity. In addition to DNMT3A’s previously characterised chromatin reader domains, a UDR motif forms contacts with the nucleosome surface. These all work multivalently to ensure correct intragenic recruitment. The UDR motif interacts with multiple interfaces on the nucleosome promoting direct specific reading of H2A Lys-119 ubiquitylation. DNMT3A shows a disconnect between nucleosome recruitment and methylation activity: H2AK119ub nucleosomes bind more tightly but are less efficient substrates than H3K36me2-modified nucleosomes. A UDR motif in DNMT3A acts in concert with other chromatin reading regions to promote chromatin recruitment. A cryo-EM structure reveals that DNMT3A1 binds to H2AK119ub-marked nucleosomes through its UDR motif, although this mark does not enhance DNA methylation activity.
doi_str_mv 10.1038/s44319-024-00306-3
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Here we structurally and biochemically explore the interaction of DNMT3A1 with diverse modified nucleosomes indicative of different chromatin environments. A cryo-EM structure of the full-length DNMT3A1-DNMT3L complex with a H2AK119ub nucleosome reveals that the DNMT3A1 ubiquitin-dependent recruitment (UDR) motif interacts specifically with H2AK119ub and makes extensive contacts with the core nucleosome histone surface. This interaction facilitates robust DNMT3A1 binding to nucleosomes, and previously unexplained DNMT3A disease-associated mutations disrupt this interface. Furthermore, the UDR-nucleosome interaction synergises with other DNMT3A chromatin reading elements in the absence of histone ubiquitylation. H2AK119ub does not stimulate DNMT3A DNA methylation activity, as observed for the previously described H3K36me2 mark, which may explain low levels of DNA methylation on H2AK119ub marked facultative heterochromatin. This study highlights the importance of multivalent binding of DNMT3A to histone modifications and the nucleosome surface and increases our understanding of how DNMT3A1 chromatin recruitment occurs. Synopsis A UDR motif in DNMT3A acts in concert with other chromatin reading regions to promote chromatin recruitment. A cryo-EM structure reveals that DNMT3A1 binds to H2AK119ub-marked nucleosomes through its UDR motif, although this mark does not enhance DNA methylation activity. In addition to DNMT3A’s previously characterised chromatin reader domains, a UDR motif forms contacts with the nucleosome surface. These all work multivalently to ensure correct intragenic recruitment. The UDR motif interacts with multiple interfaces on the nucleosome promoting direct specific reading of H2A Lys-119 ubiquitylation. 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Here we structurally and biochemically explore the interaction of DNMT3A1 with diverse modified nucleosomes indicative of different chromatin environments. A cryo-EM structure of the full-length DNMT3A1-DNMT3L complex with a H2AK119ub nucleosome reveals that the DNMT3A1 ubiquitin-dependent recruitment (UDR) motif interacts specifically with H2AK119ub and makes extensive contacts with the core nucleosome histone surface. This interaction facilitates robust DNMT3A1 binding to nucleosomes, and previously unexplained DNMT3A disease-associated mutations disrupt this interface. Furthermore, the UDR-nucleosome interaction synergises with other DNMT3A chromatin reading elements in the absence of histone ubiquitylation. H2AK119ub does not stimulate DNMT3A DNA methylation activity, as observed for the previously described H3K36me2 mark, which may explain low levels of DNA methylation on H2AK119ub marked facultative heterochromatin. This study highlights the importance of multivalent binding of DNMT3A to histone modifications and the nucleosome surface and increases our understanding of how DNMT3A1 chromatin recruitment occurs. Synopsis A UDR motif in DNMT3A acts in concert with other chromatin reading regions to promote chromatin recruitment. A cryo-EM structure reveals that DNMT3A1 binds to H2AK119ub-marked nucleosomes through its UDR motif, although this mark does not enhance DNA methylation activity. In addition to DNMT3A’s previously characterised chromatin reader domains, a UDR motif forms contacts with the nucleosome surface. These all work multivalently to ensure correct intragenic recruitment. The UDR motif interacts with multiple interfaces on the nucleosome promoting direct specific reading of H2A Lys-119 ubiquitylation. DNMT3A shows a disconnect between nucleosome recruitment and methylation activity: H2AK119ub nucleosomes bind more tightly but are less efficient substrates than H3K36me2-modified nucleosomes. A UDR motif in DNMT3A acts in concert with other chromatin reading regions to promote chromatin recruitment. 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source Open Access: PubMed Central
subjects Animals
Biomedical and Life Sciences
Chromatin - genetics
Chromatin - metabolism
Cryoelectron Microscopy
DNA (Cytosine-5-)-Methyltransferases - chemistry
DNA (Cytosine-5-)-Methyltransferases - genetics
DNA (Cytosine-5-)-Methyltransferases - metabolism
DNA Methylation
DNA Methyltransferase 3A - metabolism
EMBO09
EMBO40
Histones - metabolism
Humans
Life Sciences
Models, Molecular
Nucleosomes - metabolism
Protein Binding
Ubiquitination
title The N-terminal region of DNMT3A engages the nucleosome surface to aid chromatin recruitment
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