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The Mre11/Rad50/Nbs1 Complex Limits Adeno-Associated Virus Transduction and Replication

Rachel A. Schwartz,^1,2 Jose Alejandro Palacios,³ Geoffrey D. Cassell,^1, Sarah Adam,^1, Mauro Giacca,³ and Matthew D. Weitzman^1*

Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, California 92037,¹ Biology Graduate Program, University of California, San Diego, California 92093,² Molecular Medicine Laboratory, International Center for Genetic Engineering and Biotechnology, Trieste, Italy³

Received 11 July 2007/ Accepted 17 September 2007

Adeno-associated virus (AAV) is a parvovirus with a small single-stranded DNA genome that relies on cellular replication machinery together with functions supplied by coinfecting helper viruses. The impact of host factors on AAV infection is not well understood. We explored the connection between AAV helper functions supplied by adenovirus and cellular DNA repair proteins. The adenoviral E1b55K/E4orf6 proteins induce degradation of the cellular Mre11 repair complex (MRN) to promote productive adenovirus infection. These viral proteins also augment recombinant AAV transduction and provide crucial helper functions for wild-type AAV replication. Here, we show that MRN poses a barrier to AAV and that the helper function provided by E1b55K/E4orf6 involves MRN degradation. Using a fluorescent method to visualize the viral genome, we show an effect at the viral DNA level. MRN components accumulate at AAV replication centers and recognize the viral inverted terminal repeats. Together, our data suggest that AAV is targeted by MRN and has evolved to exploit adenoviral proteins that degrade these cellular factors.

Published ahead of print on 26 September 2007.

Present address: Nativis, Inc., 10975 N. Torrey Pines Road, La Jolla, CA 92037.

Present address: Centre de Recherche Pharmapeptides, Université de Genève, Geneva, Switzerland.

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