Viral interactions with non-homologous end-joining: a game of hide-and-seek

Abstract

There are extensive interactions between viruses and the host DNA damage response (DDR) machinery. The outcome of these interactions includes not only direct effects on viral nucleic acids and genome replication, but also the activation of host stress response signalling pathways that can have further, indirect effects on viral life cycles. The non-homologous end-joining (NHEJ) pathway is responsible for the rapid and imprecise repair of DNA double-stranded breaks in the nucleus that would otherwise be highly toxic. Whilst directly repairing DNA, components of the NHEJ machinery, in particular the DNA-dependent protein kinase (DNA-PK), can activate a raft of downstream signalling events that activate antiviral, cell cycle checkpoint and apoptosis pathways. This combination of possible outcomes results in NHEJ being pro- or antiviral depending on the infection. In this review we will describe the broad range of interactions between NHEJ components and viruses and their consequences for both host and pathogen.

Keywords: DNA damage; DNA-PK; NHEJ; PRR sensing; double-stranded break; virus.

Fig. 1.

NHEJ and antiviral innate immunity. Damaged self-DNA and foreign viral DNA are both sensed by the DDR machinery (HR and NHEJ). The DDR machinery is responsible for repairing damaged DNA and ensuring survival of the cell. It also leads to the activation of a number of stress response pathways, which determine the fate of the cell, such as apoptosis/senescence, cellular antiviral state, etc. This graphic emphasizes the role of an NHEJ component, the DNA-PK complex, in antiviral immunity. DNA-PK recognizes intracellular viral DNA and activates the IFN innate immune response through activation of the STING adaptor protein or possibly via the direct phosphorylation of the IRF3 transcription factor. The indicated viral proteins suppress the innate immune response by blocking the signalling pathway at various stages. DDR, DNA damage response; HR, homologous recombination; NHEJ, non-homologous end-joining; DNA-PK, DNA-dependent protein kinase; STING, stimulator of IFN genes; IRF3, IFN regulatory factor 3; DNA-PKcs, DNA-dependent protein kinase catalytic subunit; HSV ICP0, herpes simplex virus infected cell polypeptide 0; VACV, vaccinia virus; AdV, adenovirus.

Fig. 2.

Schematic diagram of the NHEJ pathway. Ku70/80 recognize and bind to free ends of DNA at double-stranded breaks. The kinase DNA-PKcs is recruited and phosphorylates a number of downstream targets, contributing to further end-processing of the DNA. Ligase 4 in complex with XRCC4, XLF and PAXX re-ligate the broken DNA ends. Various virus types interact with proteins at multiple steps of the NHEJ pathway. DNA-PKcs, DNA-dependent protein kinase catalytic subunit; XRCC4, X-ray cross-complementing protein 4; XLF, XRCC4-like factor; PAXX, paralogue of XRCC4 and XLF.