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Published on: July 6, 2013
DNA damage responses in HCMV infection: emerging mechanisms and outstanding questions
Mamata Savanagouder1, Pierce Longmire2,3, Ahmed Hassan4
1Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA.
Abstract:
The cellular DNA damage response (DDR) is essential for maintaining genome integrity in the face of exogenous assault, as well as errors and breaks introduced during DNA replication. The DDR is a complex network of cellular processes that detects the type and severity of DNA damage and coordinates downstream actions. These include activating specific DNA repair pathways, including cell cycle arrest to allow time for repair, and-if the damage is irreparable-triggering apoptosis to eliminate cells with compromised genomes. DNA viruses have evolved multiple strategies to evade, suppress, or even hijack host DDR factors to promote their own replication. In the absence of such countermeasures, the activation of the host DDR may rapidly detect viral genomes as aberrant DNA, and restrict viral infection. Paradoxically, many DNA viruses depend on many aspects of the host DDR to ensure efficient replication of their genomes. Here, we focus on human cytomegalovirus (HCMV), a beta-herpesvirus with a large complex double-stranded DNA genome, and its relationship with host DDR. Although HCMV infects most of the human population, fundamental gaps remain in understanding how viral replication modulates a robust cellular DDR or recruits it for its own replication. Moreover, the roles of DDR in restricting viral DNA (vDNA) replication, promoting entry into latency, stabilizing latent genomes during cellular proliferation, and promoting vDNA synthesis following infection or reactivation from latency remain poorly understood.
Insights
The cellular DNA damage response (DDR) is crucial for genome stability. This study explores how human cytomegalovirus (HCMV) interacts with the DDR, highlighting gaps in understanding viral manipulation of this essential cellular process.
Area of Science:
- Molecular Biology
- Virology
- Cell Biology
Background:
- The cellular DNA damage response (DDR) maintains genome integrity against DNA damage.
- DNA viruses have evolved mechanisms to evade or utilize the host DDR for replication.
- Human cytomegalovirus (HCMV) is a widespread DNA virus with complex interactions with the host DDR.
Purpose of the Study:
- To investigate the intricate relationship between HCMV replication and the host cell's DNA damage response (DDR).
- To identify knowledge gaps concerning how viral replication modulates or hijacks DDR pathways.
- To understand the DDR's role in viral DNA replication, latency, and reactivation.
Main Methods:
- This study focuses on reviewing existing literature and identifying key research questions regarding HCMV and DDR interactions.
- Analysis of viral strategies to manipulate host DDR pathways.
- Examination of the DDR's influence on viral DNA replication and latency.
Main Results:
- HCMV infection presents a complex interplay with the host DDR, with viruses both evading and utilizing DDR components.
- Significant gaps exist in understanding how HCMV replication affects DDR signaling.
- The precise roles of DDR in viral DNA replication, latency establishment, and reactivation remain largely uncharacterized.
Conclusions:
- Further research is essential to elucidate the multifaceted interactions between HCMV and the host DDR.
- Understanding these interactions could reveal novel therapeutic targets for HCMV infection.
- Clarifying the DDR's role is critical for comprehending HCMV pathogenesis and lifecycle.
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