TOP2β-Dependent Nuclear DNA Damage Shapes Extracellular Growth Factor Responses via Dynamic AKT Phosphorylation to...

Area of Science:

• Molecular Biology
• Virology
• Cellular Signaling

Background:

• The mechanistic target of rapamycin (mTOR) pathway integrates cellular signals for growth and survival.
• Neurotropic viruses like herpes simplex virus-1 (HSV-1) utilize AKT-mTORC1 signaling for establishing viral latency.
• Understanding viral latency mechanisms is crucial for managing persistent infections.

Purpose of the Study:

• To define a novel genotoxic response integrating extracellular and nuclear signals via AKT-mTORC1.
• To investigate the role of DNA double-strand breaks (DSBs) in maintaining HSV-1 latency.
• To explore how DNA repair pathways influence HSV-1 reactivation.

Main Methods:

• Investigated AKT-mTORC1 signaling in neurons during HSV-1 latency.
• Utilized Topoisomerase 2β-DNA cleavage complex (TOP2βcc) intermediates to study DSB induction.
• Manipulated host DNA-repair pathways to assess HSV-1 reactivation.
• Examined the effect of PHLPP1 phosphatase downregulation on AKT localization and signaling.

Main Results:

• Endogenous DSBs mediated by TOP2βcc are essential for AKT-mTORC1 signaling and HSV-1 latency.
• Inhibition of DNA repair pathways removing TOP2βcc triggers HSV-1 reactivation.
• Altered AKT phosphorylation dynamics due to PHLPP1 downregulation disrupts DSB-induced reactivation.

Conclusions:

• Cellular genome integrity and environmental cues are integrated by HSV-1 for lifelong infection.
• The AKT-mTORC1 pathway acts as a crucial node for viral latency, linking DNA damage to viral persistence.
• Targeting DNA repair or AKT signaling could offer strategies to control latent viral infections.