The MRE11/RAD50/NBS1 (MRN) complex is a sensor for DNA breaks. In response to DNA breaks, MRN activates a global DNA damage response (DDR) through the kinase ATM that prevents cell cycle progression and cell proliferation. Critical to the amplification of the DDR is the phosphorylation of H2AX ([gamma]H2AX), a histone that is broadly distributed throughout cellular chromatin. Here we show that MRN-ATM activates a distinct signaling response to defend the cell against DNA viruses. We reveal a critical localized MRN-ATM response that is inactivated by Adenovirus E1B-55K/E4-ORF3 early viral oncoproteins and a subsequent MRN independent global DDR that does not impact viral replication. Using Adenovirus E1B-55K/E4-ORF3 mutants, we show that MRN binds to replicating Adenovirus genomes, where it activates a localized ATM response that prevents viral but not cellular DNA replication. In contrast to cellular DNA breaks, MRN-ATM activation on the miniscule Adenovirus genome is not amplified by [gamma]H2AX across chromatin and does not induce DDR foci and global signaling, hallmarks of cellular DNA damage. Thus, the MRN-ATM response to replicating Adenovirus genomes is uncoupled from the response to cellular DNA breaks. The uncoupling of the cellular and anti-viral MRN- ATM responses permits infected cells to divide and implies that DDR foci and signal amplification have evolved as mechanisms to distinguish 'self' and 'non-self' pathological DNA and mediate an appropriate response. Furthermore, cellular DNA breaks can sequester MRN from sensing viral genomes, thus rescuing Adenovirus genome replication. This demonstrates that that cellular DNA damage dampens the host defenses to viral replication which best explains the increased permissiveness for viral genome replication in tumor cell lines. Importantly, this work suggests that elevated genomic instability in cancer cells can be targeted for the development of oncolytic viruses that selectively replicate in cancer cells

Cytosine DNA methylation protects eukaryotic genomes by silencing transposons and harmful DNAs, but also regulates gene expression during normal development. Loss of CG methylation in the Arabidopsis thaliana met1 and ddm1 mutants causes varied and stochastic developmental defects that are often inherited independently of the original met1 or ddm1 mutation. Loss of non-CG methylation in plants with combined mutations in the DRM and CMT3 genes also causes a suite of developmental defects. We show here that the pleiotropic developmental defects of drm1 drm2 cmt3 triple mutant plants are fully recessive, and unlike phenotypes caused by met1 and ddm1, are not inherited independently of the drm and cmt3 mutations. Developmental phenotypes are also reversed when drm1 drm2 cmt3 plants are transformed with DRM2 or CMT3, implying that non-CG DNA methylation is efficiently re-established by sequence-specific signals. We provide evidence that these signals include RNA silencing though the 24-nucleotide short interfering RNA (siRNA) pathway as well as histone H3K9 methylation, both of which converge on the putative chromatin-remodeling protein DRD1. These signals act in at least three partially intersecting pathways that control the locus-specific patterning of non-CG methylation by the DRM2 and CMT3 methyltransferases. Our results suggest that non-CG DNA methylation that is inherited via a network of persistent targeting signals has been co-opted to regulate developmentally important genes.