So close yet so far apart: distinct flanking sequence recognition by DNMT3A and DNMT3B
Abstract DNMT3A and DNMT3B are closely related DNA methyltransferases that catalyze de novo CpG methylation and have distinct preferences for flanking sequences. Despite sharing 91% sequence similarity within their catalytic domains, these paralogs show non-overlapping genomic targeting and divergen...
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| Format: | Article |
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Nature Portfolio
2025-08-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-08606-7 |
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| _version_ | 1849234852110401536 |
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| author | Ayşe Berçin Barlas Ezgi Karaca |
| author_facet | Ayşe Berçin Barlas Ezgi Karaca |
| author_sort | Ayşe Berçin Barlas |
| collection | DOAJ |
| description | Abstract DNMT3A and DNMT3B are closely related DNA methyltransferases that catalyze de novo CpG methylation and have distinct preferences for flanking sequences. Despite sharing 91% sequence similarity within their catalytic domains, these paralogs show non-overlapping genomic targeting and divergent biological roles. To uncover the mechanistic basis of this specificity, we performed 16µs of all-atom molecular dynamics simulations on DNMT3A and DNMT3B complexes bound to CpG substrates with varied +2 flanking bases (i.e., CGX). To resolve their base- and shape-readout mechanisms at atomistic detail, we introduced a Comparative Dynamics Analysis (CDA) framework. Our CDA approach revealed that DNMT3A relies on a rigid, sequence-specific hydrogen bonding network and shape-constrained electrostatic anchoring, whereas DNMT3B employs a more flexible and distributed interface, allowing broader substrate tolerance. This represents the first systematic analysis of shape readout in DNMT3 enzymes and demonstrates how flanking sequence specificity is dynamically encoded by two nearly identical proteins. Our findings not only clarify how closely related DNA-modifying enzymes diverge in recognition strategies, but also lay the foundation for future efforts to engineer paralog-specific protein–DNA interactions. |
| format | Article |
| id | doaj-art-5435074673a546e99ef87c5f4be2aec3 |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-5435074673a546e99ef87c5f4be2aec32025-08-20T04:03:00ZengNature PortfolioCommunications Biology2399-36422025-08-018111410.1038/s42003-025-08606-7So close yet so far apart: distinct flanking sequence recognition by DNMT3A and DNMT3BAyşe Berçin Barlas0Ezgi Karaca1Omics and Computational Biology Program, Izmir Biomedicine and Genome CenterOmics and Computational Biology Program, Izmir Biomedicine and Genome CenterAbstract DNMT3A and DNMT3B are closely related DNA methyltransferases that catalyze de novo CpG methylation and have distinct preferences for flanking sequences. Despite sharing 91% sequence similarity within their catalytic domains, these paralogs show non-overlapping genomic targeting and divergent biological roles. To uncover the mechanistic basis of this specificity, we performed 16µs of all-atom molecular dynamics simulations on DNMT3A and DNMT3B complexes bound to CpG substrates with varied +2 flanking bases (i.e., CGX). To resolve their base- and shape-readout mechanisms at atomistic detail, we introduced a Comparative Dynamics Analysis (CDA) framework. Our CDA approach revealed that DNMT3A relies on a rigid, sequence-specific hydrogen bonding network and shape-constrained electrostatic anchoring, whereas DNMT3B employs a more flexible and distributed interface, allowing broader substrate tolerance. This represents the first systematic analysis of shape readout in DNMT3 enzymes and demonstrates how flanking sequence specificity is dynamically encoded by two nearly identical proteins. Our findings not only clarify how closely related DNA-modifying enzymes diverge in recognition strategies, but also lay the foundation for future efforts to engineer paralog-specific protein–DNA interactions.https://doi.org/10.1038/s42003-025-08606-7 |
| spellingShingle | Ayşe Berçin Barlas Ezgi Karaca So close yet so far apart: distinct flanking sequence recognition by DNMT3A and DNMT3B Communications Biology |
| title | So close yet so far apart: distinct flanking sequence recognition by DNMT3A and DNMT3B |
| title_full | So close yet so far apart: distinct flanking sequence recognition by DNMT3A and DNMT3B |
| title_fullStr | So close yet so far apart: distinct flanking sequence recognition by DNMT3A and DNMT3B |
| title_full_unstemmed | So close yet so far apart: distinct flanking sequence recognition by DNMT3A and DNMT3B |
| title_short | So close yet so far apart: distinct flanking sequence recognition by DNMT3A and DNMT3B |
| title_sort | so close yet so far apart distinct flanking sequence recognition by dnmt3a and dnmt3b |
| url | https://doi.org/10.1038/s42003-025-08606-7 |
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