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Mutagenesis Advance Access published online on October 19, 2005
Mutagenesis, doi:10.1093/mutage/gei059
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© The Author 2005. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received May 2, 2005
Revised August 27, 2005
Accepted September 27, 2005

Article

The ATPase motif in RAD51D is required for resistance to DNA interstrand crosslinking agents and interaction with RAD51C

Aaron M. Gruver 1, Kristi A. Miller 2, Changanamkandath Rajesh 1, Phillip G. Smiraldo 1, Saravanan Kaliyaperumal 1, Rachel Balder 1, Katie M. Stiles 1, Joanna S. Albala 3, and Douglas L. Pittman 1*

1 Department of Physiology and Cardiovascular Genomics, Medical University of Ohio, Toledo, OH, USA
2 Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, Livermore, CA, USA; Present address: Genentech, Inc., South San Francisco, CA, USA
3 Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, Livermore, CA, USA; Present address: University of California, Davis, Sacramento, CA, USA

* To whom correspondence should be addressed.
Douglas L. Pittman, E-mail: dpittman{at}meduohio.edu


  Abstract

Homologous recombination (HR) is a mechanism for repairing DNA interstrand crosslinks and double-strand breaks. In mammals, HR requires the activities of the RAD51 family (RAD51, RAD51B, RAD51C, RAD51D, XRCC2, XRCC3 and DMC1), each of which contains conserved ATP binding sequences (Walker Motifs A and B). RAD51D is a DNA-stimulated ATPase that interacts directly with RAD51C and XRCC2. To test the hypothesis that ATP binding and hydrolysis by RAD51D are required for the repair of interstrand crosslinks, site-directed mutations in Walker Motif A were generated, and complementation studies were performed in Rad51d-deficient mouse embryonic fibroblasts. The K113R and K113A mutants demonstrated a respective 96 and 83% decrease in repair capacity relative to wild-type. Further examination of these mutants, by yeast two-hybrid analyses, revealed an 8-fold reduction in the ability to associate with RAD51C whereas interaction with XRCC2 was retained at a level similar to the S111T control. These cell-based studies are the first evidence that ATP binding and hydrolysis by RAD51D are required for efficient HR repair of DNA interstrand crosslinks.


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