Many viruses modulate cell cycle progression to enhance their replication and persistence in the host cell In the case of oncogenic viruses, this process may ultimately lead to cellular transformation and oncogenesis. In the present study, we demonstrate that Marek's disease virus (MDV), an alphaherpesvirus responsible ofTlymphoma in chickens, is also able to subvert the cell cycle progression. Infection of primary chicken embryo skin cells with MDV triggered the re-entry of quiescent cells into the cell cycle and delayed the progression of the cell cycle into S-phase. We could also identified the tegument protein VP22 as a major MDV-encoded cell cycle regulator since its over-expression in proliferating cells led to a dramatic cell cycle arrest in S-phase. This striking functional feature of VP22 appears to be conserved among members of the Alphaherpesvirinae and is depended on its nuclear localization and histones binding capacity. The mechanism underlying the VP22 mediated S-phase arrest might rely on the ability of VP22 to generate DNA double strand breaks. Taken together, our results shed a new light on the mechanisms of MDV-induced lymphomagenesis by describing a new role for the VP22 tegument protein in viral reprogramming of the cell cycle of the host cell associated to DNA damage induction.