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Molecular and Cellular Biology, October 1998, p. 5797-5808, Vol. 18, No. 10
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Hypersensitivity of Ku-Deficient Cells toward the DNA Topoisomerase II Inhibitor ICRF-193 Suggests a Novel Role for Ku Antigen during the G2 and M Phases of the Cell Cycle

Purificación Muñoz,1,* Malgorzata Z. Zdzienicka,2 Jean-Marie Blanchard,1 and Jacques Piette1

Institut de Génétique Moléculaire de Montpellier, CNRS, 34293 Montpellier Cedex 5, France,1 and Leiden University, 2300 RA Leiden, The Netherlands2

Received 5 March 1998/Returned for modification 10 April 1998/Accepted 2 July 1998

Ku antigen is a heterodimer, comprised of 86- and 70-kDa subunits, which binds preferentially to free DNA ends. Ku is associated with a catalytic subunit of 450 kDa in the DNA-dependent protein kinase (DNA-PK), which plays a crucial role in DNA double-strand break (DSB) repair and V(D)J recombination of immunoglobulin and T-cell receptor genes. We now demonstrate that Ku86 (86-kDa subunit)-deficient Chinese hamster cell lines are hypersensitive to ICRF-193, a DNA topoisomerase II inhibitor that does not produce DSB in DNA. Mutant cells were blocked in G2 at drug doses which had no effect on wild-type cells. Moreover, bypass of this G2 block by caffeine revealed defective chromosome condensation in Ku86-deficient cells. The hypersensitivity of Ku86-deficient cells toward ICRF-193 was not due to impaired in vitro decatenation activity or altered levels of DNA topoisomerase IIalpha or -beta . Rather, wild-type sensitivity was restored by transfection of a Ku86 expression plasmid into mutant cells. In contrast to cells deficient in the Ku86 subunit of DNA-PK, cells deficient in the catalytic subunit of the enzyme neither accumulated in G2/M nor displayed defective chromosome condensation at lower doses of ICRF-193 compared to wild-type cells. Our data suggests a novel role for Ku antigen in the G2 and M phases of the cell cycle, a role that is not related to its role in DNA-PK-dependent DNA repair.

* Corresponding author. Mailing address: Institut de Génétique Moléculaire de Montpellier, CNRS, 1919 route de Mende, 34293 Montpellier Cedex 5, France. Phone: 33 4 67 61 36 46. Fax: 33 4 67 04 02 31. E-mail: munoz{at}igm.cnrs-mop.fr.

Molecular and Cellular Biology, October 1998, p. 5797-5808, Vol. 18, No. 10
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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