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Molecular and Cellular Biology, September 2003, p. 6385-6395, Vol. 23, No. 18
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.18.6385-6395.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Werner Syndrome Protein Phosphorylation by Abl Tyrosine Kinase Regulates Its Activity and Distribution

Wen-Hsing Cheng,1 Cayetano von Kobbe,1 Patricia L. Opresko,1 Kesha M. Fields,1 Jian Ren,2 Donald Kufe,2 and Vilhelm A. Bohr1*

Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224,1 Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 021152

Received 7 February 2003/ Returned for modification 2 April 2003/ Accepted 13 June 2003

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.

* Corresponding author. Mailing address: Laboratory of Molecular Gerontology, National Institute on Aging, NIH, 5600 Nathan Shock Dr., Baltimore, MD 21224. Phone: (410) 558-8162. Fax: (410) 558-8157. E-mail: vbohr{at}nih.gov.

Molecular and Cellular Biology, September 2003, p. 6385-6395, Vol. 23, No. 18
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.18.6385-6395.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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