Adenovirus oncoproteins inactivate the Mre11-Rad50-NBS1 DNA repair complex

• Published in: Nature (London) 2002-07, Vol.418 (6895), p.348-352
• Main Authors: Weitzman, Matthew D, Stracker, Travis H, Carson, Christian T
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Adenoviridae - metabolism; Adenoviridae - physiology; Adenovirus E1B Proteins - genetics; Adenovirus E1B Proteins - metabolism; Adenovirus E4 Proteins - genetics; Adenovirus E4 Proteins - metabolism; Biological and medical sciences; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - chemistry; Cell Cycle Proteins - metabolism; Cell Line; Cell Transformation, Viral; Cellular biology; Deoxyribonucleic acid; DNA; DNA Damage; DNA Repair; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - metabolism; Fluorescent Antibody Technique; Fundamental and applied biological sciences. Psychology; Fungal Proteins - antagonists & inhibitors; Fungal Proteins - metabolism; Genetics; HeLa Cells; Humans; Macromolecular Substances; Mammals; Microbiology; MRE11 Homologue Protein; Multiprotein Complexes; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - chemistry; Nuclear Proteins - metabolism; Protein Binding; Proteins; Replicative cycle, interference, host-virus relations, pathogenicity, miscellaneous strains; Saccharomyces cerevisiae Proteins; Virology; Virus Replication
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature00863

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 maintenance. 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 packaged. 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 oncoproteins.