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PMID:12944467

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Citation

Cheng, WH, von Kobbe, C, Opresko, PL, Fields, KM, Ren, J, Kufe, D and Bohr, VA (2003) Werner syndrome protein phosphorylation by abl tyrosine kinase regulates its activity and distribution. Mol. Cell. Biol. 23:6385-95

Abstract

The Werner syndrome protein (WRN) is a caretaker of the human genome, and the Abl kinase is a regulator of the DNA damage response. Aberrant DNA repair has been linked to the development of cancer. Here, we have identified a direct binding between WRN and c-Abl in vitro via the N-terminal and central regions of WRN and the Src homology domain 3 of c-Abl. After bleomycin treatment in culture, WRN and c-Abl are dissociated and followed by an Abl kinase-dependent WRN relocalization to the nucleoplasm. WRN is a substrate of c-Abl in vitro and in vivo. WRN is tyrosine phosphorylated either transiently by treatment of HeLa cells with bleomycin or constitutively in cells from chronic myeloid leukemia (CML) patients, and these phosphorylations are prevented by treatment with the Abl kinase inhibitor STI-571. Tyrosine phosphorylation of WRN results in inhibition of both WRN exonuclease and helicase activities. Furthermore, anti-WRN immunoprecipitates from CML cells treated with STI-571 show increased 3'-->5' exonuclease activity. These findings suggest a novel signaling pathway by which c-Abl mediates WRN nuclear localization and catalytic activities in response to DNA damage.

Links

PubMed PMC193690

Keywords

Animals; Binding Sites; Bleomycin/pharmacology; DNA Damage/physiology; DNA Helicases/drug effects; DNA Helicases/genetics; DNA Helicases/metabolism; Enzyme Inhibitors/pharmacology; Exodeoxyribonucleases; HeLa Cells; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology; Mice; Phosphorylation; Piperazines/pharmacology; Protein Transport/drug effects; Proto-Oncogene Proteins c-abl/antagonists & inhibitors; Proto-Oncogene Proteins c-abl/genetics; Proto-Oncogene Proteins c-abl/metabolism; Pyrimidines/pharmacology; RecQ Helicases; Recombinant Proteins/genetics; Recombinant Proteins/metabolism; Signal Transduction; Tumor Cells, Cultured; Tyrosine/metabolism; src Homology Domains

Significance

Annotations

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

MOUSE:ABL1

enables

GO:0004713: protein tyrosine kinase activity

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(MGI:MGI:109635)

Seeded From UniProt

complete

HUMAN:WRN

part_of

GO:0005654: nucleoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:WRN

part_of

GO:0005730: nucleolus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:WRN

enables

GO:0003678: DNA helicase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:WRN

enables

GO:0004527: exonuclease activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:ABL1

part_of

GO:0005730: nucleolus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:ABL1

enables

GO:0004713: protein tyrosine kinase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:NUCL

part_of

GO:0005730: nucleolus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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