title: DNA damage regulates UHRF1 stability via the SCF(β-TrCP) E3 ligase.
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 SCF(β-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 (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 enhanced S108(UHRF1) phosphorylation. Taken together, our data identify SCF(β-TrCP) as a bona fide UHRF1 E3 ligase important for regulating UHRF1 steady-state levels both under normal conditions and in response to DNA damage.
authors.affiliation: Laboratory of Epigenetics, Institute of Biomedical Sciences, and Department of Biochemistry, Fudan University Medical School, Shanghai, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.forename: Honghui
authors.initials: H
authors.lastname: Ma
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Inuzuka
authors.forename: Jianbo
authors.initials: J
authors.lastname: Diao
authors.forename: Fei
authors.initials: F
authors.lastname: Lan
authors.forename: Yujiang Geno
authors.initials: YG
authors.lastname: Shi
authors.forename: Wenyi
authors.initials: W
authors.lastname: Wei
authors.forename: Yang
authors.initials: Y
authors.lastname: Shi
mesh_terms: D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D048148:Casein Kinase Idelta / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D004249:DNA Damage; D045325:HCT116 Cells; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D010766:Phosphorylation / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D055550:Protein Stability; D059748:Proteolysis; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D014466:Ultraviolet Rays; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism*
chemical_list: C471644:BTRC protein, human; D022762:CCAAT-Enhancer-Binding Proteins; D044844:beta-Transducin Repeat-Containing Proteins; D044843:SKP Cullin F-Box Protein Ligases; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases; D048148:Casein Kinase Idelta; D046988:Proteasome Endopeptidase Complex