Rad51 activates polyomavirus JC early transcription

Area of Science:

• Neurovirology
• Molecular Biology
• Immunology

Background:

• JC virus (JCV) causes progressive multifocal leukoencephalopathy (PML), a fatal CNS disease, typically in immunocompromised individuals.
• JCV reactivation involves complex regulatory events, with the transcription factor NF-κB implicated in activating viral replication.
• Active JCV infection induces host cell DNA damage and upregulates DNA repair proteins like Rad51.

Purpose of the Study:

• To investigate the role of Rad51 in regulating JCV early transcription.
• To elucidate the mechanism by which Rad51 influences JCV gene expression in the context of NF-κB activation.

Main Methods:

• Assessed the effect of increased Rad51 expression on the JCV early promoter activity.
• Utilized NF-κB p65, NF-κB binding site mutation, siRNA knockdown, and the histone deacetylase inhibitor sodium butyrate to study regulatory interactions.
• Examined the interplay between Rad51, NF-κB, and histone acetylation in modulating JCV transcription.

Main Results:

• Increased Rad51 expression was found to activate the JCV early promoter.
• Rad51-mediated activation was cooperative with NF-κB p65 stimulation and dependent on the NF-κB binding site.
• Histone deacetylase inhibition enhanced Rad51's stimulatory effect on JCV transcription.

Conclusions:

• Rad51 induction during JCV infection stimulates viral early transcription by acting through NF-κB and its binding site.
• This represents a novel positive feedback mechanism that enhances viral gene expression during the early stages of JCV infection.
• Understanding this mechanism may offer insights into controlling JCV reactivation and PML pathogenesis.