53BP1, a known chromatin-associated factor that promotes DNA damage repair, is differentially modulated during bovine herpesvirus 1 infection in vitro and in vivo.

Bovine herpesvirus 1 (BoHV-1) productive infection induces the formation of DNA double-strand breaks (DSBs), the most severe form of DNA lesions in cultured cells. 53BP1, a chromatin-associated factor, plays an essential role in DNA damage repair. In this study, we demonstrated that BoHV-1 productive infection in bovine kidney (MDBK) cells increased the expression of phosphorylated form of H2AX protein (γH2AX) and promoted the formation of γH2AX foci in the nucleus, indicative of enhanced DNA lesions. However, despite the elevated total 53BP1 protein levels, its recruitment to the nucleus and formation of 53BP1 foci was impaired, suggesting the disruption of 53BP1-mediated DNA damage repair (DDR). Furthermore, immunohistochemistry (IHC) studies showed that γH2AX was readily detected in trigeminal ganglia (TG) neurons of New Zealand White rabbits during both acute infection (day 3) and dexamethasone (DEX)-stimulated reactivation from latency, indicating the occurrence of DNA damage in vivo. This was consistent with the substantial reduction of 53BP1 protein expression in these tissues. Interestingly, 53BP1 was detected in a subset of TG neurons from both mock-infected and latently infected rabbits, but the localization profile of 53BP1 looks largely different, suggesting that 53BP1 may play a role in viral latency. Taken together, our findings demonstrated that BoHV-1 lytic infection impaired 53BP1-dependent DNA damage repair through differing mechanisms in vitro and in vivo, potentially promoting the accumulation of DNA damage. Moreover, virus latency altered the 53BP1 localization, underscoring the importance of 53BP1 signaling in the virus pathogenicity.