Structural insights into DNMT5-mediated ATP-dependent high-fidelity epigenome maintenance Journal Article

   


Authors: Wang, J.; Catania, S.; Wang, C.; de la Cruz, M. J.; Rao, B.; Madhani, H. D.; Patel, D. J.
Article Title: Structural insights into DNMT5-mediated ATP-dependent high-fidelity epigenome maintenance
Abstract: Epigenetic evolution occurs over million-year timescales in Cryptococcus neoformans and is mediated by DNMT5, the first maintenance type cytosine methyltransferase identified in the fungal or protist kingdoms, the first dependent on adenosine triphosphate (ATP), and the most hemimethyl-DNA-specific enzyme known. To understand these novel properties, we solved cryo-EM structures of CnDNMT5 in three states. These studies reveal an elaborate allosteric cascade in which hemimethylated DNA binding first activates the SNF2 ATPase domain by a large rigid body rotation while the target cytosine partially flips out of the DNA duplex. ATP binding then triggers striking structural reconfigurations of the methyltransferase catalytic pocket to enable cofactor binding, completion of base flipping, and catalysis. Bound unmethylated DNA does not open the catalytic pocket and is instead ejected upon ATP binding, driving high fidelity. This unprecedented chaperone-like, enzyme-remodeling role of the SNF2 ATPase domain illuminates how energy is used to enable faithful epigenetic memory. © 2022 The Authors
Keywords: dna methylation; cryptococcus neoformans; atp; sam; sah; cryo-em structure; dna cytosine-5 methyltransferase; dnmt5; snf2 atpase
Journal Title: Molecular Cell
Volume: 82
Issue: 6
ISSN: 1097-2765
Publisher: Cell Press  
Date Published: 2022-01-01
Start Page: 1186
End Page: 1198.e6
Language: English
DOI: 10.1016/j.molcel.2022.01.028
PUBMED: 35202575
PROVIDER: scopus
PMCID: PMC8956514
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85126290257&doi=10.1016%2fj.molcel.2022.01.028&partnerID=40&md5=c38be118af61640eb4d549ece079d4aa
Notes: Article -- Export Date: 1 April 2022 -- Source: Scopus
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MSK Authors
  1. Dinshaw J Patel
    477 Patel
  2. Michael Jason V De La Cruz
    12 De La Cruz
  3. Chongyuan Wang
    7 Wang
  4. Juncheng Wang
    12 Wang
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