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Journal of Virology, May 2009, p. 4565-4573, Vol. 83, No. 9
0022-538X/09/$08.00+0     doi:10.1128/JVI.00042-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Temporal Regulation of the Mre11-Rad50-Nbs1 Complex during Adenovirus Infection{triangledown}

Kasey A. Karen,1 Peter J. Hoey,2,{dagger} C. S. H. Young,2 and Patrick Hearing1*

Department of Molecular Genetics and Microbiology, School of Medicine, Stony Brook University, Stony Brook, New York 11794,1 Department of Microbiology, Columbia University, 701 W. 168th Street, New York, New York 100322

Received 8 January 2009/ Accepted 16 February 2009

Adenovirus infection induces a cellular DNA damage response that can inhibit viral DNA replication and ligate viral genomes into concatemers. It is not clear if the input virus is sufficient to trigger this response or if viral DNA replication is required. Adenovirus has evolved two mechanisms that target the Mre11-Rad50-Nbs1 (MRN) complex to inhibit the DNA damage response. These include E4-ORF3-dependent relocalization of MRN proteins and E4-ORF6/E1B-55K-dependent degradation of MRN components. The literature suggests that degradation of the MRN complex due to E4-ORF6/E1B-55K does not occur until after viral DNA replication has begun. We show that, by the time viral DNA accumulates, the MRN complex is inactivated by either of the E4-induced mechanisms and that, with E4-ORF6/E1B-55K, this inactivation is due to MRN degradation. Our data are consistent with the conclusion that input viral DNA is sufficient to induce the DNA damage response. Further, we demonstrate that when the DNA damage response is active in E4 mutant virus infections, the covalently attached terminal protein is not cleaved from viral DNAs, and the viral origins of replication are not detectably degraded at a time corresponding to the onset of viral replication. The sequences of concatemeric junctions of viral DNAs were determined, which supports the conclusion that nonhomologous end joining mediates viral DNA ligation. Large deletions were found at these junctions, demonstrating nucleolytic procession of the viral DNA; however, the lack of terminal protein cleavage and terminus degradation at earlier times shows that viral genome deletion and concatenation are late effects.

* Corresponding author. Mailing address: Department of Molecular Genetics and Microbiology, School of Medicine, Stony Brook University, Stony Brook, NY 11794. Phone: (631) 632-8813. Fax: (631) 632-8891. E-mail: phearing{at}ms.cc.sunysb.edu

{triangledown} Published ahead of print on 25 February 2009.

{dagger} Present address: Freeport High School Science Department, 50 South Brookside Avenue, Freeport, NY 11520.

Journal of Virology, May 2009, p. 4565-4573, Vol. 83, No. 9
0022-538X/09/$08.00+0     doi:10.1128/JVI.00042-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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