{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T17:14:17Z","timestamp":1787073257848,"version":"build-2736575974"},"reference-count":34,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T00:00:00Z","timestamp":1774483200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Biruni University Research Center","award":["B\u0130RUN\u0130-BAP-12-2025-01-75"],"award-info":[{"award-number":["B\u0130RUN\u0130-BAP-12-2025-01-75"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Endometriosis affects approximately 10% of reproductive-age women and is associated with genomic instability; however, the contribution of specific DNA repair deficiencies remains poorly understood. This study investigated the expression and function of GEN1, a Holliday junction resolvase critical for homologous recombination, in patient-derived endometrial epithelial organoids (EEOs). Endometrial tissue was obtained by pipelle biopsy from women with laparoscopically confirmed endometriosis (n = 3, stage III\u2013IV) and controls without endometriosis (n = 3). GEN1 mRNA and protein expression were reduced in primary endometrial cells from endometriosis patients compared with controls (mRNA: 0.52 \u00b1 0.14 vs. 1.00 \u00b1 0.19, p = 0.05; immunofluorescence intensity: 0.54 \u00b1 0.18 vs. 1.00 \u00b1 0.22, p = 0.05). Patient-derived EEOs from the endometriosis group showed trends toward lower formation efficiency (18.4 \u00b1 5.6% vs. 25.2 \u00b1 6.8%, p = 0.10) and reduced mean diameter (124.6 \u00b1 34.2 vs. 155.8 \u00b1 32.6 \u00b5m, p = 0.10). RNA interference (RNAi)-mediated GEN1 knockdown reduced proliferation in both groups, with a more pronounced effect in endometriosis-derived EEOs (49.7% vs. 39.5% reduction, p = 0.05). Endometriosis-derived EEOs exhibited elevated baseline \u03b3H2AX (phosphorylated histone H2AX) immunofluorescence compared with controls (2.32 \u00b1 0.44 vs. 1.00 \u00b1 0.28, p = 0.05), indicating increased DNA double-strand break accumulation. Furthermore, GEN1 knockdown directly increased \u03b3H2AX intensity in both groups, with endometriosis-derived EEOs showing a greater absolute increase (\u03941.26 vs. \u03940.72). To our knowledge, this study provides the first organoid-based evidence that GEN1 is downregulated in endometriosis and functionally linked to impaired proliferation and elevated DNA damage, suggesting a potential contribution of homologous recombination dysregulation to endometriosis pathogenesis.<\/jats:p>","DOI":"10.3390\/ijms27073034","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T11:32:47Z","timestamp":1774611167000},"page":"3034","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Reduced GEN1 Expression Is Associated with Elevated DNA Damage and Impaired Proliferation in Endometriosis-Derived Endometrial Organoids"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1141-6381","authenticated-orcid":false,"given":"Berivan","family":"Guzelbag","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Haseki Training and Research Hospital, Health Sciences University, 34270 Istanbul, T\u00fcrkiye"},{"name":"Department of Molecular and Medical Genetics, Institute of Graduate Studies, Biruni University, 34020 Istanbul, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1868-4140","authenticated-orcid":false,"given":"Nazli Ece","family":"Gungor","sequence":"additional","affiliation":[{"name":"Histology and Embryology Department, Medical School, Biruni University, 34020 Istanbul, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hadice","family":"Karahan","sequence":"additional","affiliation":[{"name":"Molecular Biology and Genetics Department, Faculty of Natural Sciences and Engineering, Biruni University, 34020 Istanbul, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2697-4296","authenticated-orcid":false,"given":"Alireza","family":"Maghsoudi","sequence":"additional","affiliation":[{"name":"Department of Stem Cell and Tissue Engineering, Graduate School of Health Sciences, Istinye University, 34010 Istanbul, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4123-6357","authenticated-orcid":false,"given":"Engin","family":"Oral","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Norrland University Hospital, Ume\u00e5 University, 90187 Umea, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/S0140-6736(21)00389-5","article-title":"Endometriosis is a chronic systemic disease: Clinical challenges and novel innovations","volume":"397","author":"Taylor","year":"2021","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1056\/NEJMra1810764","article-title":"Endometriosis","volume":"382","author":"Zondervan","year":"2020","journal-title":"N. 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