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Building on previous evidence linking SMYD3 to DNA damage repair, we investigated the molecular mechanisms through which SMYD3 regulates double-strand break (DSB) repair in GC and evaluated its therapeutic potential.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In silico and in vitro analyses were performed to investigate the interactions between SMYD3 and key homologous recombination (HR) proteins, and to evaluate the ATM-mediated phosphorylation of SMYD3. Functional assays assessed the impact of pharmacological SMYD3 inhibition on HR and non-homologous end joining (NHEJ) repair pathways.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Mechanistically, SMYD3 interacted with key HR factors and facilitated chromatin remodeling at damaged sites. ATM phosphorylated SMYD3 at threonine 22, a modification required for HR complex assembly and validated in GC patient samples following neoadjuvant chemotherapy. Inhibition of SMYD3 abolished HR and partially impaired NHEJ. Combined inhibition of SMYD3 and PARP induced synthetic lethality in GC cells, spheroids, and patient-derived organoids, and overcame resistance to olaparib.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings reveal the ATM-dependent molecular mechanism by which SMYD3 regulates DNA DSB repair, further supporting SMYD3 as a promising therapeutic target for precision oncology strategies in GC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13046-026-03823-2","type":"journal-article","created":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T04:44:01Z","timestamp":1789188241000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting the DNA-repair chromatin-modifier protein SMYD3 as a novel epigenetics-based therapy for gastric cancer"],"prefix":"10.1186","volume":"45","author":[{"given":"Katia","family":"De Marco","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marialaura","family":"Latrofa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Forte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Lepore Signorile","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Di Nicola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Sanese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Candida","family":"Fasano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vittoria","family":"Disciglio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"Candela","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Coletta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Grossi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristiano","family":"Simone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,12]]},"reference":[{"key":"3823_CR1","doi-asserted-by":"publisher","first-page":"3020","DOI":"10.1038\/s41591-025-03793-6","volume":"31","author":"JY Park","year":"2025","unstructured":"Park JY, Georges D, Alberts CJ, Bray F, Clifford G, Baussano I. 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