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TitleStructures of USP7 in active and inactive states bound to DNMT1 revealed by cryo-EM.
Journal, issue, pagesStructure, Vol. 33, Issue 9, Page 1510-11518.e5, Year 2025
Publish dateSep 4, 2025
AuthorsNao Nakamura / Sae Yoshimi / Amika Kikuchi / Hiroki Onoda / Satomi Kori / Makoto Nakanishi / Atsuya Nishiyama / Kyohei Arita /
PubMed AbstractThe ubiquitin signal generated by UHRF1 is essential for DNA methylation maintenance by recruiting DNA methyltransferase 1 (DNMT1) to hemimethylated DNA through strong binding of its replication foci ...The ubiquitin signal generated by UHRF1 is essential for DNA methylation maintenance by recruiting DNA methyltransferase 1 (DNMT1) to hemimethylated DNA through strong binding of its replication foci targeting sequence (RFTS) domain to ubiquitinated histone H3. The ubiquitin-specific protease 7 (USP7) forms a complex with DNMT1 and removes ubiquitin from H3. However, it remains unknown how USP7 deubiquitinates ubiquitinated H3 upon strong binding of the DNMT1 RFTS domain. Here, we show the activation mechanism of USP7 by combining biochemical and structural studies. USP7 is inactive toward ubiquitinated H3 in complex with the RFTS domain. However, when complexed with DNMT1, USP7 efficiently deubiquitinates ubiquitinated H3. Cryogenic electron microscopy (cryo-EM) single particle analysis revealed that USP7 bound to DNMT1 undergoes an open (inactive) and closed (active) conformational transition. Our findings provide mechanistic insights into the activation of USP7 upon binding to DNMT1 and contribute to a better understanding of the deubiquitination process in DNA methylation maintenance.
External linksStructure / PubMed:40645181
MethodsEM (single particle)
Resolution3.54 - 3.75 Å
Structure data

EMDB-61999, PDB-9k2w:
Cryo-EM structure of USP7:DNMT1 complex; closed conformation
Method: EM (single particle) / Resolution: 3.54 Å

EMDB-62000, PDB-9k2x:
Cryo-EM structure of USP7:DNMT1 complex; open conformation
Method: EM (single particle) / Resolution: 3.75 Å

Chemicals

ChemComp-ZN:
Unknown entry

Source
  • homo sapiens (human)
KeywordsSTRUCTURAL PROTEIN / DNA methylation / deubiquitination

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