RESUMEN
In response to cellular genome breaks, MRE11/RAD50/NBS1 (MRN) activates a global ATM DNA damage response (DDR) that prevents cellular replication. Here, we show that MRN-ATM also has critical functions in defending the cell against DNA viruses. We reveal temporally distinct responses to adenovirus genomes: a critical MRN-ATM DDR that must be inactivated by E1B-55K/E4-ORF3 viral oncoproteins and a global MRN-independent ATM DDR to viral nuclear domains that does not impact viral replication. We show that MRN binds to adenovirus genomes and activates a localized ATM response that specifically prevents viral DNA replication. In contrast to chromosomal breaks, ATM activation is not amplified by H2AX across megabases of chromatin to induce global signaling and replicative arrest. Thus, γH2AX foci discriminate "self" and "non-self" genomes and determine whether a localized anti-viral or global ATM response is appropriate. This provides an elegant mechanism to neutralize viral genomes without jeopardizing cellular viability.
Asunto(s)
Infecciones por Adenoviridae/inmunología , Reparación del ADN , Genoma Viral , Adenoviridae/genética , Adenoviridae/fisiología , Proteínas E1B de Adenovirus/metabolismo , Proteínas E4 de Adenovirus/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Línea Celular Tumoral , Células Cultivadas , Proteínas de Unión al ADN/metabolismo , Genoma Humano , Histonas/metabolismo , Humanos , Fosforilación , Replicación ViralRESUMEN
Arising from: S. J. Lolle, J. L. Victor, J. M. Young & R. E. Pruitt 434, 505-509 (2005); Lolle et al. reply. Lolle et al. report that loss-of-function alleles of the HOTHEAD (HTH) gene in Arabidopsis thaliana are genetically unstable, giving rise to wild-type revertants. On the basis of the reversion of many other genetic markers in hth plants, they suggested a model in which a cache of extragenomic information could cause genes to revert to the genotype of previous generations. In our attempts to reproduce this phenomenon, we discovered that hth mutants show a marked tendency to outcross (unlike wild-type A. thaliana, which is almost exclusively self-fertilizing). Moreover, when hth plants are grown in isolation, their genetic inheritance is completely stable. These results may provide an alternative explanation for the genome wide non-mendelian inheritance reported by Lolle et al.