SCF-FBXO31 E3 ligase targets DNA replication factor Cdt1 for proteolysis in the G2 phase of cell cycle to prevent re-replication.
FBXO31 was originally identified as a putative tumor suppressor gene in breast, ovarian, hepatocellular, and prostate cancers. By screening a set of cell cycle-regulated proteins as potential FBXO31 interaction partners, we have now identified Cdt1 as a novel substrate. Cdt1 DNA replication licensing factor is part of the pre-replication complex and essential for the maintenance of genomic integrity. We show that FBXO31 specifically interacts with Cdt1 and regulates its abundance by ubiquitylation leading to subsequent degradation. We also show that Cdt1 regulation by FBXO31 is limited to the G2 phase of the cell cycle and is independent of the pathways previously described for Cdt1 proteolysis in S and G2 phase. FBXO31 targeting of Cdt1 is mediated through the N terminus of Cdt1, a region previously shown to be responsible for its cell cycle regulation. Finally, we show that Cdt1 stabilization due to FBXO31 depletion results in re-replication. Our data present an additional pathway that contributes to the FBXO31 function as a tumor suppressor.
From the Sahlgrenska University Hospital, Department of Clinical Chemistry, Bruna Stråket 16, 41345 Gothenburg, Sweden.
Pegah
P
Johansson
Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
Jessie
J
Jeffery
Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
Fares
F
Al-Ejeh
Centre for Personalised Cancer Medicine and Discipline of Medicine, University of Adelaide, Adelaide, South Australia 5000, Australia.
Renèe B
RB
Schulz
Centre for Personalised Cancer Medicine and Discipline of Medicine, University of Adelaide, Adelaide, South Australia 5000, Australia.
David F
DF
Callen
School of Paediatrics and Reproductive Health and Discipline of Medicine, University of Adelaide, Adelaide and Women's and Children's Health Research Institute, North Adelaide, South Australia 5006, Australia, and raman.sharma@adelaide.edu.au.
Raman
R
Kumar
Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia KumKum.Khanna@qimrberghofer.edu.au.
Kum Kum
KK
Khanna
D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D016195:G2 Phase; D006801:Humans; D011485:Protein Binding; D059748:Proteolysis; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
C467199:CDT1 protein, human; D018797:Cell Cycle Proteins; D044783:F-Box Proteins; C507917:FBXO31 protein, human; D025521:Tumor Suppressor Proteins
Cdt1; Cell Cycle; DNA Replication; E3 Ubiquitin Ligase; FBXO31; Genomic Instability; Protein Degradation