In response to cellular genome breaks, a group of proteins called MRN activates a global ATM DNA damage response (DDR) that prevents cellular replication.
Researchers show in the journal Cell that MRN-ATM also has critical functions in defending the cell against DNA viruses.
Authors reveal temporally distinct responses to adenovirus genomes: a critical MRN-ATM DDR that must be inactivated by viral oncoproteins (E1B-55K/E4-ORF3 ) and a global MRN-independent ATM DDR to viral nuclear domains that does not impact viral replication.
They 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.