{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T22:50:05Z","timestamp":1785279005288,"version":"3.55.0"},"reference-count":60,"publisher":"American Society for Microbiology","issue":"7","license":[{"start":{"date-parts":[[2024,7,23]],"date-time":"2024-07-23T00:00:00Z","timestamp":1721692800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/doi.org\/10.1128\/ASMCopyrightv2"},{"start":{"date-parts":[[2024,7,23]],"date-time":"2024-07-23T00:00:00Z","timestamp":1721692800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"HHS | National Institutes of Health","award":["U01 CA275310, R01 DE032623"],"award-info":[{"award-number":["U01 CA275310, R01 DE032623"]}]},{"name":"DHS","award":["70 RSAT 19 CB 0000027"],"award-info":[{"award-number":["70 RSAT 19 CB 0000027"]}]},{"DOI":"10.13039\/100009168","name":"USDA | Animal and Plant Health Inspection Service","doi-asserted-by":"crossref","award":["6000027242"],"award-info":[{"award-number":["6000027242"]}],"id":[{"id":"10.13039\/100009168","id-type":"DOI","asserted-by":"crossref"}]},{"name":"HHS | National Institutes of Health","award":["U01 CA275310, R01 DE032623"],"award-info":[{"award-number":["U01 CA275310, R01 DE032623"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2024,7,23]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>Treatment options for Epstein-Barr virus (EBV)-cancers are limited, underscoring the need for new therapeutic approaches. We have previously shown that EBV-transformed cells and cancers lack homologous recombination (HR) repair, a prominent error-free pathway that repairs double-stranded DNA breaks; instead, EBV-transformed cells demonstrate genome-wide scars of the error-prone microhomology-mediated end joining (MMEJ) repair pathway. This suggests that EBV-cancers are vulnerable to synthetic lethal therapeutic approaches that target MMEJ repair. Indeed, we have previously found that targeting PARP, an enzyme that contributes to MMEJ, results in the death of EBV-lymphoma cells. With the emergence of clinical resistance to PARP inhibitors and the recent discovery of inhibitors of Polymerase theta (POL\u03b8), the polymerase essential for MMEJ, we investigated the role of POL\u03b8 in EBV-lymphoma cells. We report that EBV-transformed cell lines, EBV-lymphoma cell lines, and EBV-lymphomas in AIDS patients demonstrate greater abundance of POL\u03b8, driven by the EBV protein EBNA1, compared to EBV-uninfected primary lymphocytes and EBV-negative lymphomas from AIDS patients (a group that also abundantly expresses POL\u03b8). We also find POL\u03b8 enriched at cellular DNA replication forks and exposure to the POL\u03b8 inhibitor Novobiocin impedes replication fork progress, impairs MMEJ-mediated repair of DNA double-stranded breaks, and kills EBV-lymphoma cells. Notably, cell killing is not due to Novobiocin-induced activation of the lytic\/replicative phase of EBV. These findings support a role for POL\u03b8 not just in DNA repair but also DNA replication and as a therapeutic target in EBV-lymphomas and potentially other EBV-cancers as EBNA1 is expressed in all EBV-cancers.<\/jats:p>\n            <jats:sec>\n              <jats:title>IMPORTANCE<\/jats:title>\n              <jats:p>Epstein-Barr virus (EBV) contributes to ~2% of the global cancer burden. With a recent estimate of &gt;200,000 deaths a year, identifying molecular vulnerabilities will be key to the management of these frequently aggressive and treatment-resistant cancers. Building on our earlier work demonstrating reliance of EBV-cancers on microhomology-mediated end-joining repair, we now report that EBV lymphomas and transformed B cell lines abundantly express the MMEJ enzyme POL\u03b8 that likely protects cellular replication forks and repairs replication-related cellular DNA breaks. Importantly also, we show that a newly identified POL\u03b8 inhibitor kills EBV-cancer cells, revealing a novel strategy to block DNA replication and repair of these aggressive cancers.<\/jats:p>\n            <\/jats:sec>\n          <\/jats:sec>","DOI":"10.1128\/jvi.00572-24","type":"journal-article","created":{"date-parts":[[2024,6,11]],"date-time":"2024-06-11T13:05:40Z","timestamp":1718111140000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":9,"title":["Polymerase theta is a synthetic lethal target for killing Epstein-Barr virus lymphomas"],"prefix":"10.1128","volume":"98","author":[{"given":"Griffin H.","family":"Willman","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases, Department of Pediatrics, University of Florida, Gainesville, Florida, 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