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Molecular and Cellular Biology, April 1999, p. 2986-2997, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Role for Caspase-Mediated Cleavage of Rad51 in Induction of Apoptosis by DNA Damage

YinYin Huang,1 Shuji Nakada,1 Takatoshi Ishiko,1 Taiju Utsugisawa,1 Rakesh Datta,1 Surender Kharbanda,1 Kiyotsugu Yoshida,1 Robert V. Talanian,2 Ralph Weichselbaum,3 Donald Kufe,1,* and Zhi-Min Yuan1

Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 021151; BASF Bioresearch Corp., Worcester, Massachusetts 016052; and Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois 606373

Received 29 July 1998/Returned for modification 18 September 1998/Accepted 15 December 1998

We report here that the Rad51 recombinase is cleaved in mammalian cells during the induction of apoptosis by ionizing radiation (IR) exposure. The results demonstrate that IR induces Rad51 cleavage by a caspase-dependent mechanism. Further support for involvement of caspases is provided by the finding that IR-induced proteolysis of Rad51 is inhibited by Ac-DEVD-CHO. In vitro studies show that Rad51 is cleaved by caspase 3 at a DVLD/N site. Stable expression of a Rad51 mutant in which the aspartic acid residues were mutated to alanines (AVLA/N) confirmed that the DVLD/N site is responsible for the cleavage of Rad51 in IR-induced apoptosis. The functional significance of Rad51 proteolysis is supported by the finding that, unlike intact Rad51, the N- and C-terminal cleavage products fail to exhibit recombinase activity. In cells, overexpression of the Rad51(D-A) mutant had no effect on activation of caspase 3 but did abrogate in part the apoptotic response to IR exposure. We conclude that proteolytic inactivation of Rad51 by a caspase-mediated mechanism contributes to the cell death response induced by DNA damage.

* Corresponding author. Mailing address: Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney St., Boston, MA 02115. Phone: (617) 632-3141. Fax: (617) 632-2934. E-mail: donald_kufe{at}dfci.harvard.edu.

Molecular and Cellular Biology, April 1999, p. 2986-2997, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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