Cleavage and inactivation of ATM during apoptosis.

Abstract

The activation of the cysteine proteases with aspartate specificity, termed caspases, is of fundamental importance for the execution of programmed cell death. These proteases are highly specific in their action and activate or inhibit a variety of key protein molecules in the cell. Here, we study the effect of apoptosis on the integrity of two proteins that have critical roles in DNA damage signalling, cell cycle checkpoint controls, and genome maintenance-the product of the gene defective in ataxia telangiectasia, ATM, and the related protein ATR. We find that ATM but not ATR is specifically cleaved in cells induced to undergo apoptosis by a variety of stimuli. We establish that ATM cleavage in vivo is dependent on caspases, reveal that ATM is an efficient substrate for caspase 3 but not caspase 6 in vitro, and show that the in vitro caspase 3 cleavage pattern mirrors that in cells undergoing apoptosis. Strikingly, apoptotic cleavage of ATM in vivo abrogates its protein kinase activity against p53 but has no apparent effect on the DNA binding properties of ATM. These data suggest that the cleavage of ATM during apoptosis generates a kinase-inactive protein that acts, through its DNA binding ability, in a trans-dominant-negative fashion to prevent DNA repair and DNA damage signalling.

• Authors: G C Smith, F d'Adda di Fagagna, N D Lakin, S P Jackson
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 19 Issue 9 Pg. 6076-84 (Sep 1999) ISSN: 0270-7306 [Print] United States
• PMID: 10454555 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• DNA Primers
• DNA-Binding Proteins
• Enzyme Inhibitors
• Proteins
• Recombinant Fusion Proteins
• Topoisomerase II Inhibitors
• Tumor Suppressor Protein p53
• Tumor Suppressor Proteins
• Etoposide
• DNA
• ATM protein, human
• ATR protein, human
• Ataxia Telangiectasia Mutated Proteins
• Protein Serine-Threonine Kinases
• CASP3 protein, human
• CASP6 protein, human
• Caspase 3
• Caspase 6
• Caspases

Topics

• Amino Acid Sequence
• Apoptosis (drug effects, genetics, physiology)
• Ataxia Telangiectasia (genetics, metabolism)
• Ataxia Telangiectasia Mutated Proteins
• Base Sequence
• Binding Sites
• Caspase 3
• Caspase 6
• Caspases (metabolism)
• Cell Cycle Proteins (genetics, metabolism)
• DNA (genetics, metabolism)
• DNA Damage
• DNA Primers (genetics)
• DNA Repair
• DNA-Binding Proteins
• Enzyme Inhibitors (pharmacology)
• Epitope Mapping
• Etoposide (pharmacology)
• HL-60 Cells
• HeLa Cells
• Humans
• Protein Binding
• Protein Serine-Threonine Kinases
• Proteins (antagonists & inhibitors, genetics, metabolism)
• Recombinant Fusion Proteins (genetics, metabolism)
• Signal Transduction
• Topoisomerase II Inhibitors
• Tumor Suppressor Protein p53 (metabolism)
• Tumor Suppressor Proteins