Abstract
The presence of the Epstein-Barr virus (EBV)-encoded nuclear antigen-1 (EBNA1) protein in all EBV-carrying tumours constitutes a marker that distinguishes the virus-associated cancer cells from normal cells and thereby offers opportunities for targeted therapeutic intervention. EBNA1 is essential for viral genome maintenance and also for controlling viral gene expression and without EBNA1, the virus cannot persist. EBNA1 itself has been linked to cell transformation but the underlying mechanism of its oncogenic activity has been unclear. However, recent data are starting to shed light on its growth-promoting pathways, suggesting that targeting EBNA1 can have a direct growth suppressing effect. In order to carry out its tasks, EBNA1 interacts with cellular factors and these interactions are potential therapeutic targets, where the aim would be to cripple the virus and thereby rid the tumour cells of any oncogenic activity related to the virus. Another strategy to target EBNA1 is to interfere with its expression. Controlling the rate of EBNA1 synthesis is critical for the virus to maintain a sufficient level to support viral functions, while at the same time, restricting expression is equally important to prevent the immune system from detecting and destroying EBNA1-positive cells. To achieve this balance EBNA1 has evolved a unique repeat sequence of glycines and alanines that controls its own rate of mRNA translation. As the underlying molecular mechanisms for how this repeat suppresses its own rate of synthesis in cis are starting to be better understood, new therapeutic strategies are emerging that aim to modulate the translation of the EBNA1 mRNA. If translation is induced, it could increase the amount of EBNA1-derived antigenic peptides that are presented to the major histocompatibility (MHC) class I pathway and thus, make EBV-carrying cancers better targets for the immune system. If translation is further suppressed, this would provide another means to cripple the virus.
Highlights
Epstein-Barr virus (EBV) nuclear antigen-1 (EBNA1) is an essential viral protein and is expressed in all EBV-associated tumours as well as all latency programs of the virus, except perhaps for latency 0.It exerts essential functions in viral DNA replication and the episomal genome maintenance, achieved through sequence-specific DNA binding
OriP is composed of two functional elements localized 1 kbp apart from one another: the family of repeats (FR) and the dyad symmetry (DS) element [54] (Figure 2)
Their proximity varies according to their location within the cell nucleus as well as the phase of the cell cycle: during interphase, the two proteins appear to be colocalising throughout the cell nucleus, Förster resonance energy transfer (FRET) could only be observed at the periphery of the nucleus. The meaning of this interaction at this particular region of the nucleus remains to be determined; during mitosis, FRET was mainly observed in metaphase, indicating a more specific role for the regulator of chromosome condensation 1 (RCC1)-EBNA1 interaction at this particular stage of mitosis that precedes segregation of sister chromatids [96]. This observation, together with the overlap between the EBNA1 RCC1-interacting regions and the EBNA1 domains previously characterized for their role in chromosome binding and episome maintenance (Figure 1), argue for an important role for RCC1 in EBV episome tethering to the chromosomes and subsequent episome maintenance
Summary
Epstein-Barr virus (EBV) nuclear antigen-1 (EBNA1) is an essential viral protein and is expressed in all EBV-associated tumours as well as all latency programs of the virus, except perhaps for latency 0. It exerts essential functions in viral DNA replication and the episomal genome maintenance, achieved through sequence-specific DNA binding. More recent works shed new light on how this pleiotropic protein exerts its functions and on its oncogenic activity as well as how it regulates its own synthesis in order to evade recognition of the host cells by the immune system. This review is aimed at illustrating how these different insights open new therapeutic approaches aimed at targeting EBV-associated cancers
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