Chen H, Ma H, Inuzuka H, Diao J, Lan F, Shi YG, Wei W, Shi Y

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. Dys-regulation of UHRF1 level is implicated in cancer onset, metastasis and tumor recurrence. Previous studies demonstrated that UHRF1 can be stabilized through USP7-mediated deubiquitylation, but ...

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the mechanism of how UHRF1 is ubiquitylated is still unknown. Here we show that proteasomal degradation of UHRF1 is mediated by the SCF(β-TrCP) E3 ligase. Through bioinformatics and mutagenesis studies, we identified a functional DSG degron in the UHRF1 N-terminus necessary for UHRF1 stability regulation. We further show that UHRF1 physically interacts with β-TrCP1 in a manner dependent on phosphorylation of serine 108 (S108(UHRF1)) within the DSG degron. Furthermore, we demonstrate that S108(UHRF1) phosphorylation is catalyzed by casein kinase 1 delta (CK1δ) and is important for the recognition of UHRF1 by SCF(β-TrCP). Importantly, we demonstrate that UHRF1 degradation is accelerated in response to DNA damage, coincident with an enhanced S108(UHRF1) phosphorylation. Taken together, we identified SCF(β-TrCP) as a bona fide UHRF1 E3 ligase important for regulating UHRF1 steady state level under both normal conditions and in response to DNA damage.

Date: Jan. 07, 2013

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