{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T16:09:02Z","timestamp":1791130142923,"version":"4.1.0"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>\n                    Translesion synthesis (TLS) is a DNA damage tolerance pathway that enables cells to replicate across damaged DNA, thereby promoting cell survival under genotoxic stress, however, contributing to genomic instability and therapy resistance. C#3 is a small molecule that disrupts the interaction between MAD2L2 and Rev1, a key complex required for DNA polymerase \u03b6-mediated TLS. Here, we further investigated the impact of C#3 on MAD2L2-dependent TLS activity and cellular responses to DNA damage. Consistent with our previous findings, C#3 enhanced cellular sensitivity to cisplatin in multiple cancer cell lines and increased DNA damage signaling following treatment. Using a non-replicating plasmid assay, we demonstrate that C#3 impairs lesion bypass across DNA adducts in mammalian cells. Disruption of the MAD2L2-Rev1 axis was further supported by reduced formation of MAD2L2-Rev1 complexes, as assessed by proximity ligation assay. Functionally, cells exposed to C#3 during recovery from cisplatin treatment exhibited persistent \u03b3H2AX signaling, consistent with delayed resolution of replication-associated DNA damage.\n                    <jats:italic>In-vivo<\/jats:italic>\n                    , combined treatment with C#3 and cisplatin reduced tumor growth in syngeneic melanoma and triple-negative breast cancer mouse models compared with either treatment alone. Together, these findings demonstrate that pharmacological disruption of the MAD2L2-Rev1 axis impairs TLS associated DNA damage tolerance, enhances cellular responses to cisplatin-induced DNA damage, and suppresses tumor growth\n                    <jats:italic>in-vivo<\/jats:italic>\n                    . These results support targeting MAD2L2-dependent TLS as a potential strategy for improving the efficacy of DNA damaging chemotherapy.\n                  <\/jats:p>","DOI":"10.3389\/fcell.2026.1859193","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T06:02:13Z","timestamp":1785304933000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting MAD2L2-dependent translesion synthesis impairs DNA damage tolerance and enhances cellular response to cisplatin"],"prefix":"10.3389","volume":"14","author":[{"given":"Philippa Jennifer","family":"Ayiku","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Medicine, Ariel University","place":["Ariel, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nomi","family":"Barda","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Medicine, Ariel University","place":["Ariel, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orly Eva","family":"Weiss","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Medicine, Ariel University","place":["Ariel, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Sherman","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Medicine, Ariel University","place":["Ariel, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana","family":"Litvinov","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Medicine, Ariel University","place":["Ariel, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Fozailoff","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Medicine, Ariel University","place":["Ariel, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ido","family":"Dromi","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Sciences, Weizmann Institute of Science","place":["Rehovot, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gadi","family":"Turgeman","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Medicine, Ariel University","place":["Ariel, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamar","family":"Listovsky","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Medicine, Ariel University","place":["Ariel, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1016\/j.molcel.2006.03.022","article-title":"p53 and p21 regulate error-prone DNA repair to yield a lower mutation load","volume":"22","author":"Avkin","year":"2006","journal-title":"Mol. 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