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TitleUSP1/UAF1 targets polyubiquitinated PCNA with an exo-cleavage mechanism that can temporarily enrich for monoubiquitinated PCNA.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 6991, Year 2025
Publish dateJul 30, 2025
AuthorsNiels Keijzer / Jan Sakoltchik / Kaustav Majumder / Nina van Lil / Farid El Oualid / Alexander Fish / Titia K Sixma /
PubMed AbstractDNA damage tolerance (DDT) is an important pathway that allows cells to bypass DNA lesions during replication. DDT is orchestrated by ubiquitination of PCNA, where monoubiquitinated PCNA (PCNA-Ub) ...DNA damage tolerance (DDT) is an important pathway that allows cells to bypass DNA lesions during replication. DDT is orchestrated by ubiquitination of PCNA, where monoubiquitinated PCNA (PCNA-Ub) initiates recruitment of TLS polymerases but also serves as a substrate for further ubiquitination, forming K63-polyubiquitinated PCNA that leads to HR-mediated bypass mechanisms. Recent work on USP1/UAF1 inhibition revealed that formation of K48-linked chains also occurs on PCNA, resulting in its proteasomal degradation. USP1/UAF1 is established as deubiquitinating enzyme (DUB) for PCNA-Ub, but little is known about removal of ubiquitin chains on PCNA. Here we show that USP1/UAF1 cleaves both K48 and K63-linked ubiquitin chains on PCNA efficiently, using an exo-cleavage mechanism. Kinetic analysis reveals that USP1/UAF1 prefers cleaving the ubiquitin-ubiquitin bond over cleavage of the ubiquitin-PCNA bond and therefore treats poly- and monoubiquitinated PCNA as different substrates. A cryo-EM structure of USP1/UAF1 with a K63-diubiquitin and structure-based mutagenesis suggests that this mechanistic preference is maintained in evolution. This unusual mechanism can cause temporal enrichment of monoubiquitinated PCNA during polyubiquitination. It will be interesting to see how this affects DDT pathway balance.
External linksNat Commun / PubMed:40739138 / PubMed Central
MethodsEM (single particle)
Resolution3.04 Å
Structure data

52316

9hnw

EMDB-52316, PDB-9hnw:
USP1-UAF1 bound to Lys63-linked diubiquitin
Method: EM (single particle) / Resolution: 3.04 Å

Chemicals

ChemComp-ZN:
Unknown entry

Source
  • homo sapiens (human)
KeywordsHYDROLASE / USP1 / deubiquitinating enzyme / cysteine protease / complex

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