Werner syndrome protein phosphorylation by abl tyrosine kinase regulates its activity and distribution.
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.
Cheng
Wen-Hsing
WH
Laboratory of Molecular Gerontology, National Institute on Aging/NIH, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
von Kobbe
Cayetano
C
Opresko
Patricia L
PL
Fields
Kesha M
KM
Ren
Jian
J
Kufe
Donald
D
Bohr
Vilhelm A
VA
D000818:Animals; D001549:Benzamides; D001665:Binding Sites; D001761:Bleomycin / Q000494:pharmacology; D004249:DNA Damage / Q000502:physiology; D004265:DNA Helicases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005090:Exodeoxyribonucleases; D006367:HeLa Cells; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology; D051379:Mice; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D053484:RecQ Helicases; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D000071657:Werner Syndrome Helicase; D018909:src Homology Domains
D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D011994:Recombinant Proteins; D001761:Bleomycin; D014443:Tyrosine; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl; D005090:Exodeoxyribonucleases; D004265:DNA Helicases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase