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A Simple, Rapid, and Quantitative Assay to Measure Repair of DNA-protein Crosslinks on Plasmids Transfected into Mammalian Cells
Published on: March 5, 2018
Adenovirus oncoproteins inactivate the Mre11-Rad50-NBS1 DNA repair complex
Travis H Stracker1, Christian T Carson, Matthew D Weitzman
1Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
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 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.
Insights
The Mre11-Rad50-NBS1 complex is crucial for repairing DNA double-strand breaks. Adenovirus E4 proteins inactivate this complex, preventing viral DNA concatemer formation and promoting cell transformation.
Area of Science:
- Molecular Biology
- Virology
- Genetics
Background:
- The Mre11-Rad50-NBS1 (MRN) complex is vital for DNA repair and genome stability in mammalian cells.
- Adenovirus infection can lead to the formation of large, unpackageable DNA concatemers in the absence of early region E4 (E4).
Purpose of the Study:
- To investigate the cellular proteins involved in adenovirus DNA concatemer formation.
- To understand how adenovirus E4 products inactivate these cellular proteins during infection.
Main Methods:
- Investigated the role of the Mre11-Rad50-NBS1 complex in adenovirus DNA concatemerization.
- Analyzed the localization and fate of the MRN complex during wild-type adenovirus infection.
- Identified viral oncoproteins responsible for MRN complex inactivation.
Main Results:
- Functional Mre11 and NBS1 proteins are required for adenovirus DNA concatemerization.
- The MRN complex forms foci adjacent to viral replication centers.
- Wild-type adenovirus infection leads to the reorganization and degradation of the MRN complex.
- Three viral oncoproteins mediate the inactivation of the MRN complex, preventing concatemerization.
Conclusions:
- Adenovirus utilizes viral oncoproteins to target and inactivate the host cell's MRN complex, a key player in genomic stability.
- This inactivation mechanism prevents viral DNA concatemer formation and may contribute to adenovirus-mediated 'hit-and-run' transformation.
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