Kaposi's sarcoma-associated herpesvirus (KSHV) is linked to human malignancies. The majority of tumor cells harbor latent virus, and a small percentage undergo spontaneous lytic replication. Both latency and lytic replication are important for viral pathogenesis and spread, but the cellular players involved in the switch between the two viral life-cycle phases are not clearly understood. We conducted a small interfering RNA (siRNA) screen targeting the cellular kinome and identified Tousled-like kinases (TLKs) as cellular kinases that control KSHV reactivation from latency. Upon treatment of latent KSHV-infected cells with siRNAs targeting TLKs, we saw robust viral reactivation. Knockdown of TLKs in latent KSHV-infected cells induced expression of viral lytic proteins and production of infectious virus. TLKs were also found to play a role in regulating reactivation from latency of another related oncogenic gammaherpesvirus, Epstein-Barr virus. Our results establish the TLKs as cellular repressors of gammaherpesvirus reactivation.
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