ATM engages autodegradation of the E3 ubiquitin ligase COP1 after DNA damage

David Dornan; Harumi Shimizu; Angie Mah; Tanay Dudhela; Michael Eby; Karen O'rourke; Somasekar Seshagiri; Vishva M Dixit

doi:10.1126/science.1127335

ATM engages autodegradation of the E3 ubiquitin ligase COP1 after DNA damage

Science. 2006 Aug 25;313(5790):1122-6. doi: 10.1126/science.1127335.

Authors

David Dornan¹, Harumi Shimizu, Angie Mah, Tanay Dudhela, Michael Eby, Karen O'rourke, Somasekar Seshagiri, Vishva M Dixit

Affiliation

¹ Department of Physiological Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

PMID: 16931761
DOI: 10.1126/science.1127335

Abstract

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 Ser(387) 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 Ser(387) 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 Ser(387) was required to permit p53 to become stabilized and to exert its tumor suppressor properties in response to DNA damage.

MeSH terms

Ataxia Telangiectasia Mutated Proteins
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism*
Cell Line
Cell Line, Tumor
Cell Nucleus / metabolism
Cytoplasm / metabolism
DNA Damage*
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
Escherichia coli / genetics
Escherichia coli / metabolism
Etoposide / pharmacology
Humans
Mutation
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Phosphorylation
Phosphoserine / metabolism
Proteasome Endopeptidase Complex / metabolism
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
RNA, Small Interfering
Radiation, Ionizing
Recombinant Fusion Proteins / metabolism
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*

Substances

Cell Cycle Proteins
DNA-Binding Proteins
Nuclear Proteins
RNA, Small Interfering
Recombinant Fusion Proteins
Tumor Suppressor Protein p53
Tumor Suppressor Proteins
Ubiquitin
Phosphoserine
Etoposide
COP1 protein, human
Ubiquitin-Protein Ligases
ATM protein, human
Ataxia Telangiectasia Mutated Proteins
Protein Serine-Threonine Kinases
Proteasome Endopeptidase Complex