title: Viral and Cellular Genomes Activate Distinct DNA Damage Responses.
abstract: 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.
authors: Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037-1002, USA.
authors: Govind A
authors: GA
authors: Shah
authors: Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037-1002, USA. Electronic address: oshea@salk.edu.
authors: Clodagh C
authors: CC
authors: O'Shea
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000502:physiology; D000257:Adenoviridae Infections / Q000276:immunology*; D017501:Adenovirus E1B Proteins / Q000378:metabolism; D017504:Adenovirus E4 Proteins / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D015894:Genome, Human; D016679:Genome, Viral; D006657:Histones / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation; D014779:Virus Replication
chemical_list: D017501:Adenovirus E1B Proteins; D017504:Adenovirus E4 Proteins; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins