AI Article Synopsis
- DNMT1 is a crucial enzyme for maintaining DNA methylation, but its activation mechanisms are not fully known.
- Researchers used cryo-electron microscopy to reveal the structure of DNMT1 when bound to hemimethylated DNA and ubiquitinated histone H3, identifying a key linker that aids in its activation.
- The study highlights how the linker helps shift the enzyme from an inactive to an active state, offering new insights for research and potential drug development targeting DNMT1.
Article Abstract
DNMT1 is an essential enzyme that maintains genomic DNA methylation, and its function is regulated by mechanisms that are not yet fully understood. Here, we report the cryo-EM structure of human DNMT1 bound to its two natural activators: hemimethylated DNA and ubiquitinated histone H3. We find that a hitherto unstudied linker, between the RFTS and CXXC domains, plays a key role for activation. It contains a conserved α-helix which engages a crucial "Toggle" pocket, displacing a previously described inhibitory linker, and allowing the DNA Recognition Helix to spring into the active conformation. This is accompanied by large-scale reorganization of the inhibitory RFTS and CXXC domains, allowing the enzyme to gain full activity. Our results therefore provide a mechanistic basis for the activation of DNMT1, with consequences for basic research and drug design.
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Source |
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9681727 | PMC |
| http://dx.doi.org/10.1038/s41467-022-34779-4 | DOI Listing |
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