Translesional DNA Polη Bypass of LANA-DNA Crosslinks Ensures KSHV Episome Persistence and Tumor Growth

We show here that the Kaposi’s Sarcoma- Associated Herpesvirus (KSHV) episome maintenance protein LANA can form DNA- protein crosslinks (DPCs) with the terminal repeat (TR) DNA in a cell cycle dependent manner. Targeted shRNA screening identified translesional repair DNA polymerase Polh as necessary for the stability of KSHV TR DNA and viral episome maintenance.

We found that Polh co-immunoprecipitates and co-localizes with LANA nuclear bodies. Inhibiting the enzymatic activity of Polh by small molecule provided selective cell killing of KSHV+ B-cells and inhibited tumor progression in mice xenografts. Mechanistically Polh inhibition results in both single and double strand breaks at the KSHV TR due to unresolved LANA-DNA cross-links and replication fork collapse.