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TitleStructural insight into the DNMT1 reaction cycle by cryo-electron microscopy.
Journal, issue, pagesPLoS One, Vol. 19, Issue 9, Page e0307850, Year 2024
Publish dateSep 3, 2024
AuthorsInessa De / Jonas Weidenhausen / Nestor Concha / Christoph W Müller /
PubMed AbstractDNMT1 is an essential DNA methyltransferase that catalyzes the transfer of methyl groups to CpG islands in DNA and generates a prominent epigenetic mark. The catalytic activity of DNMT1 relies on its ...DNMT1 is an essential DNA methyltransferase that catalyzes the transfer of methyl groups to CpG islands in DNA and generates a prominent epigenetic mark. The catalytic activity of DNMT1 relies on its conformational plasticity and ability to change conformation from an auto-inhibited to an activated state. Here, we present four cryo-EM reconstructions of apo DNMT1 and DNTM1: non-productive DNA, DNTM1: H3Ub2-peptide, DNTM1: productive DNA complexes. Our structures demonstrate the flexibility of DNMT1's N-terminal regulatory domains during the transition from an apo 'auto-inhibited' to a DNA-bound 'non-productive' and finally a DNA-bound 'productive' state of DNMT1. Furthermore, we address the regulation of DNMT1's methyltransferase activity by a DNMT1-selective small-molecule inhibitor and ubiquitinated histone H3. We observe that DNMT1 binds DNA in a 'non-productive' state despite the presence of the inhibitor and present the cryo-EM reconstruction of full-length DNMT1 in complex with a di-ubiquitinated H3 peptide analogue. Taken together, our results provide structural insights into the reaction cycle of DNMT1.
External linksPLoS One / PubMed:39226277 / PubMed Central
MethodsEM (single particle)
Resolution3.3 - 6.0 Å
Structure data

EMDB-18418: Human DNA methyltransferase 1
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-50795: Human DNA methyltransferase 1 in non-productive complex with DNA
Method: EM (single particle) / Resolution: 5.11 Å

EMDB-50801: Human DNA methyltransferase 1 bound to H3Ub2-peptide
Method: EM (single particle) / Resolution: 6.0 Å

EMDB-50802: Human DNA methyltransferase 1 productive DNA complex in presence of H3Ub2-peptide
Method: EM (single particle) / Resolution: 4.6 Å

Source
  • Homo sapiens (human)

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