Abstract
Herpes simplex virus 1 (HSV-1) has extensive interactions with the host DNA damage response (DDR) machinery that can be either detrimental or beneficial to the virus. Proteins in the homologous recombination pathway are known to be required for efficient replication of the viral genome, while different members of the classical non-homologous end-joining (c-NHEJ) pathway have opposing effects on HSV-1 infection. Here, we have investigated the role of the recently-discovered c-NHEJ component, PAXX (Paralogue of XRCC4 and XLF), which we found to be excluded from the nucleus during HSV-1 infection. We have established that cells lacking PAXX have an intact innate immune response to HSV-1 but show a defect in viral genome replication efficiency. Counterintuitively, PAXX−/− cells were able to produce greater numbers of infectious virions, indicating that PAXX acts to restrict HSV-1 infection in a manner that is different from other c-NHEJ factors.
Highlights
Mammalian cells have evolved mechanisms to detect and repair damaged DNA, in order to maintain genomic integrity
This study indicated that DNA-PKcs has antiviral effects and, the consequences of this interaction between DNA-PKcs and ICP0 are not fully resolved, other Non-homologous end joining (NHEJ) proteins may be involved in this interaction [32]
The Herpes simplex virus 1 (HSV-1) protein ICP0 induces degradation of DNA-PKcs, a component of the classical NHEJ (c-NHEJ) machinery that is required for sensing of viral DNA [16,17,46]
Summary
Mammalian cells have evolved mechanisms to detect and repair damaged DNA, in order to maintain genomic integrity. The most toxic DNA lesions for a cell are DNA double strand breaks (DSB). Non-homologous end joining (NHEJ) is a key process for DSB repair (Figure 1), when homologous recombination (HR), which requires the presence of an identical DNA sequence for repair, is not possible [1]. The rejoining of DNA DSBs by NHEJ is initiated when free DNA ends are bound by the Ku70/80 heterodimer, which acts as a molecular scaffold and recruits the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) [2,3,4]. X-ray cross complementing protein (XRCC4), XRCC4-like factor (XLF), and paralogue of XRCC4 and XLF (PAXX) are recruited to the Ku heterodimer [5,6,7,8,9]. PAXX is the most recently identified component of the classical NHEJ (c-NHEJ) complex, and was found due to its high degree
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