DNA damage regulates uhrf1 stability via the SCFβ-TrCP E3 ligase

Hao Chen, Honghui Ma, Hiroyuki Inuzuka, Jianbo Diao, Fei Lan, Yujiang Geno Shi, Wenyi Wei, Yang Shi

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27 Citations (Scopus)

Abstract

UHRF1 (ubiquitin-like, with PHD and RING finger domains 1) is a critical epigenetic player involved in the maintenance of DNA methylation patterns during DNA replication. Dysregulation of the UHRF1 level is implicated in cancer onset, metastasis, and tumor recurrence. Previous studies demonstrated that UHRF1 can be stabilized through USP7-mediated deubiquitylation, but the mechanism through which UHRF1 is ubiquitylated is still unknown. Here we show that proteasomal degradation of UHRF1 is mediated by the SCFβ-TrCP E3 ligase. Through bioinformatic and mutagenesis studies, we identified a functional DSG degron in the UHRF1 N terminus that is necessary for UHRF1 stability regulation. We further show that UHRF1 physically interacts with β-TrCP1 in a manner dependent on phosphorylation of serine 108 (S108UHRF1) within the DSG degron. Furthermore, we demonstrate that S108UHRF1 phosphorylation is catalyzed by casein kinase 1 delta (CK1δ) and is important for the recognition of UHRF1 by SCFβ-TrCP. Importantly, we demonstrate that UHRF1 degradation is accelerated in response to DNA damage, coincident with enhanced S108UHRF1 phosphorylation. Taken together, our data identify SCFβTrCP as a bona fide UHRF1 E3 ligase important for regulating UHRF1 steady-state levels both under normal conditions and in response to DNA damage.

Original languageEnglish
Pages (from-to)1139-1148
Number of pages10
JournalMolecular and cellular biology
Volume33
Issue number6
DOIs
Publication statusPublished - 2013 Mar

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Chen, H., Ma, H., Inuzuka, H., Diao, J., Lan, F., Shi, Y. G., Wei, W., & Shi, Y. (2013). DNA damage regulates uhrf1 stability via the SCFβ-TrCP E3 ligase. Molecular and cellular biology, 33(6), 1139-1148. https://doi.org/10.1128/MCB.01191-12