ATM Engages Autodegradation of the E3 Ubiquitin Ligase COP1 After DNA Damage

• Published in: Science (American Association for the Advancement of Science) Vol. 313; no. 5790; pp. 1122 - 1126
• Main Authors: Dornan, David, Shimizu, Harumi, Mah, Angie, Dudhela, Tanay, Eby, Michael, O'Rourke, Karen, Seshagiri, Somasekar, Dixit, Vishva M
• Format: Journal Article
• Language: English
• Published: Washington, DC American Association for the Advancement of Science 25.08.2006; The American Association for the Advancement of Science
• Subjects: Antibodies; Antimicrobials; Ataxia Telangiectasia Mutated Proteins; Bacteria; Biochemistry; Biological and medical sciences; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line; Cell Line, Tumor; Cell Nucleus - metabolism; Cellular immunity; Chromosome fragility (bloom syndrome, ataxia telangiectasia, fanconi anemia, x-linked mental retardation...); Cytoplasm - metabolism; DNA Damage; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Escherichia coli - genetics; Escherichia coli - metabolism; Etoposide - pharmacology; Fibroblasts; Genomics; Humans; Kinases; Lectins; Medical genetics; Medical sciences; Mutation; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Phosphorylation; Phosphoserine - metabolism; Proteasome Endopeptidase Complex - metabolism; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proteins; Radiation, Ionizing; Recombinant Fusion Proteins - metabolism; RNA, Small Interfering; Transfection; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Ubiquitin - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitins; Immunopathology; Skin disease; Nervous system diseases; Carbon-nitrogen ligases; Enzyme; Transferases; Genomics; p53 Protein; Cardiovascular disease; Protein A; Essential; Genetic disease; Vascular disease; Eye disease; Regulation(control); Ligases; Protein kinase; DNA; Network; Ataxia telangiectasia; Lesion; Ubiquitin-protein ligase; Tumor suppressor gene; Integrity
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1127335

The ataxia telangiectasia mutated (ATM) protein kinase is a critical component of a DNA-damage response network configured to maintain genomic integrity. The abundance of an essential downstream effecter of this pathway, the tumor suppressor protein p53, is tightly regulated by controlled degradation through COP1 and other E3 ubiquitin ligases, such as MDM2 and Pirh2; however, the signal transduction pathway that regulates the COP1-p53 axis following DNA damage remains enigmatic. We observed that in response to DNA damage, ATM phosphorylated COP1 on Ser³⁸⁷ and stimulated a rapid autodegradation mechanism. Ionizing radiation triggered an ATM-dependent movement of COP1 from the nucleus to the cytoplasm, and ATM-dependent phosphorylation of COP1 on Ser³⁸⁷ was both necessary and sufficient to disrupt the COP1-p53 complex and subsequently to abrogate the ubiquitination and degradation of p53. Furthermore, phosphorylation of COP1 on Ser³⁸⁷ was required to permit p53 to become stabilized and to exert its tumor suppressor properties in response to DNA damage.