Abstract
In mammalian cells, a conserved multiprotein complex of Mre11, Rad50 and NBS1 (also known as nibrin and p95) is important for double-strand break repair, meiotic recombination and telomere maintenance1,2,3,4. This complex forms nuclear foci and may be a sensor of double-strand breaks. In the absence of the early region E4, the double-stranded DNA genome of adenovirus is joined into concatemers too large to be packaged5,6. We have investigated the cellular proteins involved in this concatemer formation and how they are inactivated by E4 products during a wild-type infection. Here we show that concatemerization requires functional Mre11 and NBS1, and that these proteins are found at foci adjacent to viral replication centres. Infection with wild-type virus results in both reorganization and degradation of members of the Mre11–Rad50–NBS1 complex. These activities are mediated by three viral oncoproteins that prevent concatemerization. This targeting of cellular proteins involved in genomic stability suggests a mechanism for ‘hit-and-run’ transformation observed for these viral oncoproteins7.
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Acknowledgements
We thank G. Ketner for the E4 mutant viruses and W162 cells, I. Verma for retrovirus constructs and cell lines, T. Paull for cDNAs; B. Gilbert for technical assistance; S. Malpel for complemented NBS cells; J. Bailis for advice on PFGE; M. Blower and the Center for Cytometry and Molecular Imaging at the Salk Institute for deconvolution assistance; J. Simon for help with figures; J. Weitzman, M. Grifman, T. Cathomen, C. Barlow, R. Bushman and S. Forsburg for critically reading the manuscript; R. Evans, T. Hunter, G. Wahl, B. Sefton, D. Spector, T. de Lange and J. Petrini for discussions; S. Stampfer for encouragement; and the James B. Pendleton Charitable Trust for providing the Pendelton Microscopy Facility. M.D.W. is supported in part by a grant from NIH, and by gifts from the Joe W. & Dorothy Dorsett Brown Foundation and the Lebensfeld Foundation. T.S. was supported by an NIH Graduate Training Grant to UCSD, and by fellowships from the Chapman Foundation, the Legler Benbough Foundation and the Salk Institute Association.
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Stracker, T., Carson, C. & Weitzman, M. Adenovirus oncoproteins inactivate the Mre11–Rad50–NBS1 DNA repair complex. Nature 418, 348–352 (2002). https://doi.org/10.1038/nature00863
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DOI: https://doi.org/10.1038/nature00863
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