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PMID:15790808

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Citation

Lee, JH and Paull, TT (2005) ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Science 308:551-4

Abstract

The ataxia-telangiectasia mutated (ATM) kinase signals the presence of DNA double-strand breaks in mammalian cells by phosphorylating proteins that initiate cell-cycle arrest, apoptosis, and DNA repair. We show that the Mre11-Rad50-Nbs1 (MRN) complex acts as a double-strand break sensor for ATM and recruits ATM to broken DNA molecules. Inactive ATM dimers were activated in vitro with DNA in the presence of MRN, leading to phosphorylation of the downstream cellular targets p53 and Chk2. ATM autophosphorylation was not required for monomerization of ATM by MRN. The unwinding of DNA ends by MRN was essential for ATM stimulation, which is consistent with the central role of single-stranded DNA as an evolutionarily conserved signal for DNA damage.

Links

PubMed Online version:10.1126/science.1108297

Keywords

Amino Acid Substitution; Cell Cycle Proteins/chemistry; Cell Cycle Proteins/genetics; Cell Cycle Proteins/metabolism; Cell Line; DNA/chemistry; DNA/metabolism; DNA Damage; DNA Repair; DNA Repair Enzymes/genetics; DNA Repair Enzymes/metabolism; DNA, Single-Stranded/metabolism; DNA-Binding Proteins/chemistry; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Dimerization; Enzyme Activation; Humans; Mutation; Nuclear Proteins/genetics; Nuclear Proteins/metabolism; Nucleic Acid Conformation; Phosphorylation; Protein Binding; Protein-Serine-Threonine Kinases/chemistry; Protein-Serine-Threonine Kinases/metabolism; Recombinant Proteins/metabolism; Serine; Signal Transduction; Transfection; Tumor Suppressor Proteins/chemistry; Tumor Suppressor Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:NBN

involved_in

GO:0033674: positive regulation of kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NBN

involved_in

GO:0032508: DNA duplex unwinding

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NBN

involved_in

GO:0031954: positive regulation of protein autophosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MRE11

contributes_to

GO:0003678: DNA helicase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:ATM

enables

GO:0042802: identical protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13315

F

Seeded From UniProt

complete

HUMAN:RAD50

involved_in

GO:0033674: positive regulation of kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:RAD50

involved_in

GO:0032508: DNA duplex unwinding

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:RAD50

involved_in

GO:0031954: positive regulation of protein autophosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:RAD50

contributes_to

GO:0003678: DNA helicase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:RAD50

enables

GO:0003677: DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:ATM

enables

GO:0046983: protein dimerization activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:ATM

involved_in

GO:0046777: protein autophosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ATM

enables

GO:0044877: protein-containing complex binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:ATM

involved_in

GO:0006974: cellular response to DNA damage stimulus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ATM

enables

GO:0004677: DNA-dependent protein kinase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:MRE11

involved_in

GO:0032508: DNA duplex unwinding

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MRE11

involved_in

GO:0031954: positive regulation of protein autophosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MRE11

part_of

GO:0030870: Mre11 complex

ECO:0000303: author statement without traceable support used in manual assertion

C

Seeded From UniProt

complete

HUMAN:MRE11

contributes_to

GO:0004003: ATP-dependent DNA helicase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:MRE11

contributes_to

GO:0003677: DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:MRE11

involved_in

GO:0033674: positive regulation of kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MRE11

enables

GO:0004518: nuclease activity

ECO:0000304: author statement supported by traceable reference used in manual assertion

F

Seeded From UniProt

complete


See also

References

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