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Nucleic Acids Research Advance Access published online on November 29, 2008
Nucleic Acids Research, doi:10.1093/nar/gkn934
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Nucleic Acid Enzymes

Casein kinase I {delta}/{varepsilon} phosphorylates topoisomerase II{alpha} at serine-1106 and modulates DNA cleavage activity

Adrian G. Grozav1, Kenichi Chikamori1, Toshiyuki Kozuki1, Dale R. Grabowski1, Ronald M. Bukowski1, Belinda Willard2, Michael Kinter2, Anni H. Andersen3, Ram Ganapathi1 and Mahrukh K. Ganapathi1,*

1Clinical Pharmacology Program, Taussig Cancer Institute, 2Lerner Research Institute, Department of Cell Biology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA and 3Department of Molecular Biology, Aarhus University, Aarhus, Denmark

*To whom correspondence should be addressed. Tel: +1 216 445 8416; Fax: +1 216 444 7115; Email: ganapam{at}ccf.org

Received September 12, 2008. Revised November 4, 2008. Accepted November 5, 2008.

We previously reported that phosphorylation of topoisomerase (topo) II{alpha} at serine-1106 (Ser-1106) regulates enzyme activity and sensitivity to topo II-targeted drugs. In this study we demonstrate that phosphorylation of Ser-1106, which is flanked by acidic amino acids, is regulated in vivo by casein kinase (CK) I{delta} and/or CKI{varepsilon}, but not by CKII. The CKI inhibitors, CKI-7 and IC261, reduced Ser-1106 phosphorylation and decreased formation of etoposide-stabilized topo II–DNA cleavable complex. In contrast, the CKII inhibitor, 5,6-dichlorobenzimidazole riboside, did not affect etoposide-stabilized topo II–DNA cleavable complex formation. Since, IC261 specifically targets the Ca2+-regulated isozymes, CKI{delta} and CKI{varepsilon}, we examined the effect of down-regulating these enzymes on Ser-1106 phosphorylation. Down-regulation of these isozymes with targeted si-RNAs led to hypophosphorylation of the Ser-1106 containing peptide. However, si-RNA-mediated down-regulation of CKII{alpha} and {alpha}' did not alter Ser-1106 phosphorylation. Furthermore, reduced phosphorylation of Ser-1106, observed in HRR25 (CKI{delta}/{varepsilon} homologous gene)-deleted Saccharomyces cerevisiae cells transformed with human topo II{alpha}, was enhanced following expression of human CKI{varepsilon}. Down-regulation of CKI{delta} and CKI{varepsilon} also led to reduced formation of etoposide stabilized topo II–DNA cleavable complex. These results provide strong support for an essential role of CKI{delta}/{varepsilon} in phosphorylating Ser-1106 in human topo II{alpha} and in regulating enzyme function.

Present addresses: Kenichi Chikamori, NHO Sanyo Hospital, 685 Higashi-Kiwa, Ube, Yamaguchi 755-0241, Japan Michael Kinter, Free Radical Biology and Aging Research Program, MS 21, Oklahoma Medical Research Foundation, 825 N.E. 13th Street, Oklahoma City, OK 73104, USA


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