PARP1-MEDIATED EPIGENETIC CONTROL OF LATENCY AND LYTIC REACTIVATION OF THE EPSTEIN BARR VIRUS

Abstract

Epstein Barr virus (EBV) is a gammaherpesvirus that infects more than 95% of the human population worldwide. EBV latent infection of B cells is associated with a variety of lymphomas and epithelial cancers and accounts for approximately 1% of all human cancers. The EBV genome persists in infected host cells as a chromatinized episome and is subject to chromatin-mediated regulation. Binding of the host insulator protein CTCF to the EBV genome has an established role in maintaining viral latency type, and in other herpesviruses, loss of CTCF binding at specific regions correlates with viral reactivation. CTCF is post-translationally modified by the host enzyme PARP1, which can affect CTCF’s insulator activity, DNA binding capacity, and ability to form chromatin loops. Both PARP1 and CTCF have been implicated in the regulation of EBV latency and lytic reactivation. Here, we show that PARP activity regulates CTCF in type III EBV latency to maintain latency type-specific gene expression. Further, PARP1 supports chromatin looping between the OriP enhancer and other regions throughout the EBV genome. Further, we show that CTCF is not involved in EBV lytic reactivation, although it is known to restrict reactivation in other herpesviruses. Both PARP activity and PARP1 binding function to restrict EBV lytic reactivation in response to physiological lytic induction. Overall, we show that PARP1 has specific functions throughout the EBV genome, and CTCF function is specifically regulated by PARP activity at specific loci. Taken together, we suggest a model in which PARP1 acts as a stress sensor to determine the fate of the virus in the host cell. These data provide a mechanistic understanding of PARP1 function throughout the EBV genome that suggest potential therapeutic application of PARP inhibitors in EBV-associated treatment strategies. We propose two distinct strategies specific to EBV latency type that could target EBV-infected cancer cells beyond the current chemotherapeutic standard-of-care.