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Journal of Virology, July 2007, p. 7034-7040, Vol. 81, No. 13
0022-538X/07/$08.00+0     doi:10.1128/JVI.00029-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Adenovirus E4 34k and E1b 55k Oncoproteins Target Host DNA Ligase IV for Proteasomal Degradation{triangledown}

Amy Baker,1 Kent J. Rohleder,1,{dagger} Les A. Hanakahi,2 and Gary Ketner1*

W. Harry Feinstone Department of Molecular Microbiology and Immunology,1 Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, Maryland 212052

Received 5 January 2007/ Accepted 18 April 2007

Cells infected by adenovirus E4 mutants accumulate end-to-end concatemers of the viral genome that are assembled from unit-length viral DNAs by nonhomologous end joining (NHEJ). Genome concatenation can be prevented by expression either of E4 11k (product of E4orf3) or of the complex of E4 34k (product of E4orf6) and E1b 55k. Both E4 11k and the E4 34k/E1b 55k complex prevent concatenation at least in part by inactivation of the host protein Mre11: E4 11k sequesters Mre11 in aggresomes, while the E4 34k/E1b 55k complex participates in a virus-specific E3 ubiquitin ligase that mediates ubiquitination and proteasomal degradation. The E4 34k/E1b 55k complex, but not E4 11k, also inhibits NHEJ activity on internal breaks in the viral genome and on V(D)J recombination substrate plasmids, suggesting that it may interfere with NHEJ independently of its effect on Mre11. We show here that DNA ligase IV, which performs the joining step of NHEJ, is degraded as a consequence of adenovirus infection. Degradation is dependent upon E4 34k and E1b 55k, functional proteasomes, and the activity of cellular cullin 5, a component of the adenoviral ubiquitin ligase. DNA ligase IV also interacts physically with E1b 55k. The data demonstrate that DNA ligase IV, like Mre11, is a substrate for the adenovirus-specific E3 ubiquitin ligase; identify an additional viral approach to prevention of genome concatenation; and provide a mechanism for the general inhibition of NHEJ by adenoviruses.

* Corresponding author. Mailing address: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205. Phone: (410) 955-3776. Fax: (410) 955-0105. E-mail: gketner{at}jhsph.edu

{triangledown} Published ahead of print on 25 April 2007.

{dagger} Present address: Department of Biology, Fort Hays State University, 600 Park St., Hays, KS 67601.

Journal of Virology, July 2007, p. 7034-7040, Vol. 81, No. 13
0022-538X/07/$08.00+0     doi:10.1128/JVI.00029-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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