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PMID:19716789

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Citation

Zhang, YW, Brognard, J, Coughlin, C, You, Z, Dolled-Filhart, M, Aslanian, A, Manning, G, Abraham, RT and Hunter, T (2009) The F box protein Fbx6 regulates Chk1 stability and cellular sensitivity to replication stress. Mol. Cell 35:442-53

Abstract

ATR and Chk1 are two key protein kinases in the replication checkpoint. Activation of ATR-Chk1 has been extensively investigated, but checkpoint termination and replication fork restart are less well understood. Here, we report that DNA damage not only activates Chk1, but also exposes a degron-like region at the carboxyl terminus of Chk1 to an Fbx6-containing SCF (Skp1-Cul1-F box) E3 ligase, which mediates the ubiquitination and degradation of Chk1 and, in turn, terminates the checkpoint. The protein levels of Chk1 and Fbx6 showed an inverse correlation in both cultured cancer cells and in human breast tumor tissues. Further, we show that low levels of Fbx6 and consequent impairment of replication stress-induced Chk1 degradation are associated with cancer cell resistance to the chemotherapeutic agent, camptothecin. We propose that Fbx6-dependent Chk1 degradation contributes to S phase checkpoint termination and that a defect in this mechanism might increase tumor cell resistance to certain anticancer drugs.

Links

PubMed PMC2736145 Online version:10.1016/j.molcel.2009.06.030

Keywords

Antineoplastic Agents, Phytogenic/pharmacology; Camptothecin/pharmacology; Cell Cycle/drug effects; Cell Cycle Proteins/metabolism; Cell Death/drug effects; Cell Line, Tumor; DNA Damage; DNA Replication; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Enzyme Activation; Humans; Lysine; Neoplasms/enzymology; Neoplasms/genetics; Neoplasms/pathology; Phosphorylation; Protein Kinases/genetics; Protein Kinases/metabolism; Protein Processing, Post-Translational; Protein Structure, Tertiary; Protein-Serine-Threonine Kinases/metabolism; RNA Interference; SKP Cullin F-Box Protein Ligases/genetics; SKP Cullin F-Box Protein Ligases/metabolism; Stress, Physiological; Time Factors; Ubiquitination

Significance

Annotations

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

HUMAN:CHK1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9NRD1

F

Seeded From UniProt

complete

HUMAN:FBX6

involved_in

GO:0031146: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FBX6

part_of

GO:0019005: SCF ubiquitin ligase complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:FBX6

part_of

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:FBX6

involved_in

GO:0006281: DNA repair

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

P

Seeded From UniProt

complete

HUMAN:FBX6

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:FBX6

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O14757

F

Seeded From UniProt

complete

HUMAN:CHK1

involved_in

GO:0000077: DNA damage checkpoint

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CHK1

involved_in

GO:0006281: DNA repair

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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