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PMID:14657349

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Citation

Wang, Y and Qin, J (2003) MSH2 and ATR form a signaling module and regulate two branches of the damage response to DNA methylation. Proc. Natl. Acad. Sci. U.S.A. 100:15387-92

Abstract

The mismatch repair proteins function upstream in the DNA damage signaling pathways induced by the DNA methylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). We report that MSH2 (MutS homolog 2) protein interacts with the ATR (ATM- and Rad3-related) kinase to form a signaling module and regulate the phosphorylation of Chk1 and SMC1 (structure maintenance of chromosome 1). We found that phosphorylation of Chk1 by ATR also requires checkpoint proteins Rad17 and replication protein A. In contrast, phosphorylation of SMC1 by ATR is independent of Rad17 and replication protein A, suggesting that the signaling pathway leading to SMC1 phosphorylation is distinct from that mediated by the checkpoint proteins. In addition, both MSH2 and Rad17 are required for the activation of the S-phase checkpoint to suppress DNA synthesis in response to MNNG, and phosphorylation of SMC1 is required for cellular survival. These data support a model in which MSH2 and ATR function upstream to regulate two branches of the response pathway to DNA damage caused by MNNG.

Links

PubMed PMC307577 Online version:10.1073/pnas.2536810100

Keywords

Base Pair Mismatch; Cell Cycle Proteins/drug effects; Cell Cycle Proteins/metabolism; Cell Line; Cell Survival; DNA Damage; DNA Methylation; DNA Repair/drug effects; DNA-Binding Proteins/metabolism; HeLa Cells; Humans; Kinetics; Methylnitronitrosoguanidine/pharmacology; MutS Homolog 2 Protein; Phosphorylation; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins/metabolism; Signal Transduction/physiology

Significance

Annotations

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

HUMAN:MSH3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P43246

F

Seeded From UniProt

complete

HUMAN:MSH2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P20585

F

Seeded From UniProt

complete

HUMAN:MSH2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8WXE1

F

Seeded From UniProt

complete

HUMAN:MSH2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P52701

F

Seeded From UniProt

complete

HUMAN:MSH6

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P43246

F

Seeded From UniProt

complete

HUMAN:ATR

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P43246

F

Seeded From UniProt

complete

HUMAN:ATRIP

involved_in

GO:0000077: DNA damage checkpoint

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

P

Seeded From UniProt

complete

HUMAN:ATRIP

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P43246

F

Seeded From UniProt

complete

HUMAN:MSH2

enables

GO:0019901: protein kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13535

F

Seeded From UniProt

complete

HUMAN:ATR

involved_in

GO:0000077: DNA damage checkpoint

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ATR

enables

GO:0004672: protein kinase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:ATR

involved_in

GO:0008156: negative regulation of DNA replication

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:RAD17

involved_in

GO:0008156: negative regulation of DNA replication

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:RAD17

involved_in

GO:0042325: regulation of phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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