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Virology. 2018 May;518:221-231. doi: 10.1016/j.virol.2018.02.023. Epub 2018 Mar 15.

Serotype-specific restriction of wild-type adenoviruses by the cellular Mre11-Rad50-Nbs1 complex.

Author information

1
Cell and Molecular Biology Graduate Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Division of Protective Immunity, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
2
Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Division of Protective Immunity, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: weitzmanm@email.chop.edu.

Abstract

During viral replication in the nucleus, the DNA genomes of adenoviruses are accessible to cellular DNA-binding proteins. Human adenovirus type 5 (Ad5) targets the cellular Mre11-Rad50-Nbs1 complex (MRN) to evade detection by the DNA damage response (DDR). Ad5 mutants that cannot target MRN have reduced viral propagation. Previous studies showed that diverse adenovirus serotypes interact differently with MRN. While these studies revealed diverse MRN interactions among serotypes, it remains unclear how these differences influence viral replication. Here, we examined effects of the DDR on several adenovirus serotypes. We demonstrate that wild-type Ad9 and Ad12 do not overcome MRN impairment. We also examined viral proteins involved in targeting MRN and found that unlike Ad5-E4orf3, expression of Ad9-E4orf3 is not sufficient for MRN mislocalization observed during infection. We conclude that adenovirus serotypes target MRN in distinct ways, and the MRN complex can impair DNA replication of wild-type viruses across the adenovirus family.

KEYWORDS:

ATM; Adenovirus; DNA damage response; E4orf3; MRN; Serotypes

PMID:
29547809
PMCID:
PMC5911183
[Available on 2019-05-01]
DOI:
10.1016/j.virol.2018.02.023
[Indexed for MEDLINE]

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