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Degradation of Cdc25A by β-TrCP during S phase and in response to DNA damage

Author

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  • Luca Busino

    (European Institute of Oncology)

  • Maddalena Donzelli

    (European Institute of Oncology)

  • Massimo Chiesa

    (European Institute of Oncology)

  • Daniele Guardavaccaro

    (New York University School of Medicine and NYU Cancer Institute)

  • Dvora Ganoth

    (Technion-Israel Institute of Technology)

  • N. Valerio Dorrello

    (New York University School of Medicine and NYU Cancer Institute)

  • Avram Hershko

    (Technion-Israel Institute of Technology)

  • Michele Pagano

    (New York University School of Medicine and NYU Cancer Institute)

  • Giulio F. Draetta

    (European Institute of Oncology)

Abstract

The Cdc25A phosphatase is essential for cell-cycle progression because of its function in dephosphorylating cyclin-dependent kinases. In response to DNA damage or stalled replication, the ATM and ATR protein kinases activate the checkpoint kinases Chk1 and Chk2, which leads to hyperphosphorylation of Cdc25A1,2,3. These events stimulate the ubiquitin-mediated proteolysis of Cdc25A1,4,5 and contribute to delaying cell-cycle progression, thereby preventing genomic instability1,2,3,4,5,6,7. Here we report that β-TrCP is the F-box protein that targets phosphorylated Cdc25A for degradation by the Skp1/Cul1/F-box protein complex. Downregulation of β-TrCP1 and β-TrCP2 expression by short interfering RNAs causes an accumulation of Cdc25A in cells progressing through S phase and prevents the degradation of Cdc25A induced by ionizing radiation, indicating that β-TrCP may function in the intra-S-phase checkpoint. Consistent with this hypothesis, suppression of β-TrCP expression results in radioresistant DNA synthesis in response to DNA damage—a phenotype indicative of a defect in the intra-S-phase checkpoint that is associated with an inability to regulate Cdc25A properly. Our results show that β-TrCP has a crucial role in mediating the response to DNA damage through Cdc25A degradation.

Suggested Citation

  • Luca Busino & Maddalena Donzelli & Massimo Chiesa & Daniele Guardavaccaro & Dvora Ganoth & N. Valerio Dorrello & Avram Hershko & Michele Pagano & Giulio F. Draetta, 2003. "Degradation of Cdc25A by β-TrCP during S phase and in response to DNA damage," Nature, Nature, vol. 426(6962), pages 87-91, November.
  • Handle: RePEc:nat:nature:v:426:y:2003:i:6962:d:10.1038_nature02082
    DOI: 10.1038/nature02082
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    1. Sile F. Yang & Christopher B. Nelson & Jadon K. Wells & Madushan Fernando & Robert Lu & Joshua A. M. Allen & Lisa Malloy & Noa Lamm & Vincent J. Murphy & Joel P. Mackay & Andrew J. Deans & Anthony J. , 2024. "ZNF827 is a single-stranded DNA binding protein that regulates the ATR-CHK1 DNA damage response pathway," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Alizee Lebeau & Diane Bruyere & Patrick Roncarati & Paul Peixoto & Eric Hervouet & Gael Cobraiville & Bernard Taminiau & Murielle Masson & Carmen Gallego & Gabriel Mazzucchelli & Nicolas Smargiasso & , 2022. "HPV infection alters vaginal microbiome through down-regulating host mucosal innate peptides used by Lactobacilli as amino acid sources," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    3. Reyaz ur Rasool & Caitlin M. O’Connor & Chandan Kanta Das & Mohammed Alhusayan & Brijesh Kumar Verma & Sehbanul Islam & Ingrid E. Frohner & Qu Deng & Erick Mitchell-Velasquez & Jaya Sangodkar & Aqila , 2023. "Loss of LCMT1 and biased protein phosphatase 2A heterotrimerization drive prostate cancer progression and therapy resistance," Nature Communications, Nature, vol. 14(1), pages 1-24, December.
    4. Giulia Cova & Juliane Glaser & Robert Schöpflin & Cesar Augusto Prada-Medina & Salaheddine Ali & Martin Franke & Rita Falcone & Miriam Federer & Emanuela Ponzi & Romina Ficarella & Francesca Novara & , 2023. "Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve split-hand/foot malformation type 3," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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