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Visualizing and Quantifying Endonuclease-Based Site-Specific DNA Damage
Published on: August 21, 2021
Viral and Cellular Genomes Activate Distinct DNA Damage Responses
Govind A Shah1, Clodagh C O'Shea1
1Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037-1002, USA.
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.
Insights
The MRE11/RAD50/NBS1-ATM pathway defends against adenovirus by halting viral DNA replication. This localized response, distinct from global DNA damage responses, prevents viral proliferation without harming the cell.
Area of Science:
- Molecular Biology
- Virology
- Cellular Biology
Background:
- The MRE11/RAD50/NBS1 (MRN) complex and ATM kinase are crucial for cellular DNA damage response (DDR) to genomic breaks, halting replication.
- Viruses have evolved mechanisms to evade host cell defenses, including DDR pathways.
Purpose of the Study:
- To investigate the role of the MRN-ATM pathway in defending against DNA virus infection, specifically adenovirus.
- To elucidate the distinct mechanisms by which MRN-ATM responds to viral genomes versus chromosomal breaks.
Main Methods:
- Investigated MRN-ATM interactions with adenovirus genomes.
- Analyzed the impact of viral oncoproteins (E1B-55K/E4-ORF3) on MRN-ATM signaling.
- Assessed the role of H2AX in discriminating between self and non-self genomes during DDR.
Main Results:
- MRN binds to adenovirus genomes, initiating a localized ATM response that inhibits viral DNA replication.
- Adenovirus oncoproteins E1B-55K/E4-ORF3 inactivate the MRN-ATM DDR to permit viral replication.
- A separate, MRN-independent ATM DDR targets viral nuclear domains but does not impede viral replication.
- H2AX foci formation distinguishes viral from chromosomal DNA, dictating localized anti-viral or global DDR.
Conclusions:
- The MRN-ATM pathway provides a critical, localized defense against adenovirus DNA replication.
- Viral strategies to inactivate MRN-ATM are essential for successful adenovirus infection.
- H2AX-mediated discrimination of viral genomes allows for targeted antiviral responses, preserving cellular viability.
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