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

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.