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PMID:20932473

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Citation

Reinhardt, HC, Hasskamp, P, Schmedding, I, Morandell, S, van Vugt, MA, Wang, X, Linding, R, Ong, SE, Weaver, D, Carr, SA and Yaffe, MB (2010) DNA damage activates a spatially distinct late cytoplasmic cell-cycle checkpoint network controlled by MK2-mediated RNA stabilization. Mol. Cell 40:34-49

Abstract

Following genotoxic stress, cells activate a complex kinase-based signaling network to arrest the cell cycle and initiate DNA repair. p53-defective tumor cells rewire their checkpoint response and become dependent on the p38/MK2 pathway for survival after DNA damage, despite a functional ATR-Chk1 pathway. We used functional genetics to dissect the contributions of Chk1 and MK2 to checkpoint control. We show that nuclear Chk1 activity is essential to establish a G(2)/M checkpoint, while cytoplasmic MK2 activity is critical for prolonged checkpoint maintenance through a process of posttranscriptional mRNA stabilization. Following DNA damage, the p38/MK2 complex relocalizes from nucleus to cytoplasm where MK2 phosphorylates hnRNPA0, to stabilize Gadd45α mRNA, while p38 phosphorylates and releases the translational inhibitor TIAR. In addition, MK2 phosphorylates PARN, blocking Gadd45α mRNA degradation. Gadd45α functions within a positive feedback loop, sustaining the MK2-dependent cytoplasmic sequestration of Cdc25B/C to block mitotic entry in the presence of unrepaired DNA damage. Our findings demonstrate a critical role for the MK2 pathway in the posttranscriptional regulation of gene expression as part of the DNA damage response in cancer cells.

Links

PubMed PMC3030122 Online version:10.1016/j.molcel.2010.09.018

Keywords

3' Untranslated Regions; Active Transport, Cell Nucleus; Antibiotics, Antineoplastic/pharmacology; Cell Cycle/drug effects; Cell Cycle/genetics; Cell Cycle/radiation effects; Cell Cycle Proteins/genetics; Cell Nucleus/enzymology; Cytoplasm/enzymology; DNA Damage; DNA Repair; Doxorubicin/pharmacology; Exoribonucleases/metabolism; Feedback, Physiological; HeLa Cells; Head and Neck Neoplasms/enzymology; Head and Neck Neoplasms/genetics; Heterogeneous-Nuclear Ribonucleoproteins/metabolism; Humans; Intracellular Signaling Peptides and Proteins/genetics; Intracellular Signaling Peptides and Proteins/metabolism; Mitosis; Nuclear Proteins/genetics; Phosphorylation; Protein Kinases/metabolism; Protein-Serine-Threonine Kinases/genetics; Protein-Serine-Threonine Kinases/metabolism; RNA Interference; RNA Processing, Post-Transcriptional/drug effects; RNA Processing, Post-Transcriptional/radiation effects; RNA Stability/drug effects; RNA Stability/radiation effects; RNA, Messenger/metabolism; RNA-Binding Proteins/metabolism; Signal Transduction; Time Factors; Transfection; Ultraviolet Rays; cdc25 Phosphatases/metabolism; p38 Mitogen-Activated Protein Kinases/metabolism

Significance

Annotations

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

HUMAN:PARN

enables

GO:0019901: protein kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P49137

F

Seeded From UniProt

complete

HUMAN:MAPK2

part_of

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:MAPK2

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:MAPK2

involved_in

GO:0070935: 3'-UTR-mediated mRNA stabilization

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MAPK2

enables

GO:0004674: protein serine/threonine kinase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:MAPK2

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:MAPK2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13151

F

Seeded From UniProt

complete

HUMAN:MAPK2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O95453

F

Seeded From UniProt

complete

HUMAN:ROA0

enables

GO:0019901: protein kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P49137

F

Seeded From UniProt

complete

HUMAN:ROA0

involved_in

GO:0070935: 3'-UTR-mediated mRNA stabilization

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

P

Seeded From UniProt

complete

HUMAN:ROA0

enables

GO:0035925: mRNA 3'-UTR AU-rich region binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:MK14

enables

GO:0004707: MAP kinase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:MK14

involved_in

GO:0070935: 3'-UTR-mediated mRNA stabilization

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

P

Seeded From UniProt

complete

HUMAN:CHK1

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:CHK1

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:CHK1

involved_in

GO:0072425: signal transduction involved in G2 DNA damage checkpoint

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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