{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T16:28:13Z","timestamp":1786552093085,"version":"build-2736575974"},"reference-count":35,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,4,9]],"date-time":"2021-04-09T00:00:00Z","timestamp":1617926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005640","name":"Flight Attendant Medical Research Institute","doi-asserted-by":"publisher","award":["R0502229"],"award-info":[{"award-number":["R0502229"]}],"id":[{"id":"10.13039\/100005640","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006757","name":"Office of Research and Creative Activities, Brigham Young University","doi-asserted-by":"publisher","award":["20223634"],"award-info":[{"award-number":["20223634"]}],"id":[{"id":"10.13039\/100006757","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Impaired DNA damage responses are associated with several diseases, including pregnancy complications. Recent research identified an ATM-kinase dependent function for the nuclear isoform of the receptor for advanced glycation end-products (RAGE) during double strand break (DSB)-repair. RAGE contributes to end-resectioning of broken DNA sites by binding with the MRE11-Rad50-Nbs1 (MRN) complex. Placental research is limited regarding the impact of genomic instability and the mechanism for potential repair. We tested the hypothesis regarding the involvement of RAGE during the repair of placental DNA-DSBs. We first identified that the pregnancy complications of PE and preterm labor (PTL) experience loss of genomic integrity and an in vitro trophoblast cell model was used to characterize trophoblast DSBs. Colocalized immunofluorescence of \u03b3-H2AX and RAGE support the potential involvement of RAGE in cellular responses to DNA-DSBs. Immunoblotting for both molecules in PE and PTL placenta samples and in trophoblast cells validated a connection. Co-immunoprecipitation studies revealed interactions between RAGE and pATM and MRE11 during DNA-DSBs. Reduced cellular invasion confirmed the role of genomic instability in trophoblastic function. Collectively, these experiments identified genomic instability in pregnancy complications, the impact of defective DNA on trophoblast function, and a possible RAGE-mediated mechanism during DNA-DSB repair.<\/jats:p>","DOI":"10.3390\/cells10040857","type":"journal-article","created":{"date-parts":[[2021,4,9]],"date-time":"2021-04-09T10:05:21Z","timestamp":1617962721000},"page":"857","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["A Role for RAGE in DNA Double Strand Breaks (DSBs) Detected in Pathological Placentas and Trophoblast Cells"],"prefix":"10.3390","volume":"10","author":[{"given":"Kary Y.F.","family":"Tsai","sequence":"first","affiliation":[{"name":"Lung and Placenta Research Laboratory, Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4744-8550","authenticated-orcid":false,"given":"Benton","family":"Tullis","sequence":"additional","affiliation":[{"name":"Lung and Placenta Research Laboratory, Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrina L.","family":"Breithaupt","sequence":"additional","affiliation":[{"name":"Lung and Placenta Research Laboratory, Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rylan","family":"Fowers","sequence":"additional","affiliation":[{"name":"Lung and Placenta Research Laboratory, Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelson","family":"Jones","sequence":"additional","affiliation":[{"name":"Lung and Placenta Research Laboratory, Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Grajeda","sequence":"additional","affiliation":[{"name":"Lung and Placenta Research Laboratory, Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0931-3025","authenticated-orcid":false,"given":"Paul R.","family":"Reynolds","sequence":"additional","affiliation":[{"name":"Lung and Placenta Research Laboratory, Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan A.","family":"Arroyo","sequence":"additional","affiliation":[{"name":"Lung and Placenta Research Laboratory, Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3479","DOI":"10.1007\/s00018-019-03104-6","article-title":"Human placenta and trophoblast development: Key molecular mechanisms and model systems","volume":"76","author":"Knofler","year":"2019","journal-title":"Cell Mol. Life Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1007\/s10495-017-1343-9","article-title":"Caspase dependent and independent mechanisms of apoptosis across gestation in a sheep model of placental insufficiency and intrauterine growth restriction","volume":"22","author":"Monson","year":"2017","journal-title":"Apoptosis"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"20140070","DOI":"10.1098\/rstb.2014.0070","article-title":"The role of invasive trophoblast in implantation and placentation of primates","volume":"370","author":"Carter","year":"2015","journal-title":"Philos. Trans. R. Soc. Lond. B Biol. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2152","DOI":"10.1172\/JCI119388","article-title":"Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype. One cause of defective endovascular invasion in this syndrome?","volume":"99","author":"Zhou","year":"1997","journal-title":"J. Clin. Investig."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1111\/j.1471-0528.1999.tb08107.x","article-title":"Selective deficit of angiogenic growth factors characterises pregnancies complicated by pre-eclampsia","volume":"106","author":"Reuvekamp","year":"1999","journal-title":"Br. J. Obstet. Gynaecol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1111\/aji.12327","article-title":"Placenta Growth Factor Induces Invasion and Activates p70 during Rapamycin Treatment in Trophoblast Cells","volume":"73","author":"Knuth","year":"2014","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/j.placenta.2014.09.005","article-title":"Different expression of placental pyruvate kinase in normal, preeclamptic and intrauterine growth restriction pregnancies","volume":"35","author":"Bahr","year":"2014","journal-title":"Placenta"},{"key":"ref_8","first-page":"240","article-title":"Effects of insulin on placental, fetal and maternal outcomes in gestational diabetes mellitus","volume":"30","author":"Arshad","year":"2014","journal-title":"Pak. J. Med. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e13183","DOI":"10.1111\/aji.13183","article-title":"ANXA7 regulates trophoblast proliferation and apoptosis in preeclampsia","volume":"82","author":"Mo","year":"2019","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1038\/nature08467","article-title":"The DNA-damage response in human biology and disease","volume":"461","author":"Jackson","year":"2009","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.molcel.2010.09.019","article-title":"The DNA damage response: Making it safe to play with knives","volume":"40","author":"Ciccia","year":"2010","journal-title":"Mol. Cell"},{"key":"ref_12","first-page":"a012773","article-title":"Diseases associated with defective responses to DNA damage","volume":"4","year":"2012","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.dnarep.2014.03.014","article-title":"DNA double-strand break repair pathway choice and cancer","volume":"19","author":"Aparicio","year":"2014","journal-title":"DNA Repair"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1038\/sj.cdd.4400874","article-title":"ATM, a central controller of cellular responses to DNA damage","volume":"8","author":"Khanna","year":"2001","journal-title":"Cell Death Differ"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/B978-0-12-380888-2.00003-0","article-title":"The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer","volume":"108","author":"Smith","year":"2010","journal-title":"Adv. Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1196\/annals.1433.056","article-title":"Receptor for advanced glycation end products: Fundamental roles in the inflammatory response: Winding the way to the pathogenesis of endothelial dysfunction and atherosclerosis","volume":"1126","author":"Ramasamy","year":"2008","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Lewis, J.B., Hirschi, K.M., Arroyo, J.A., Bikman, B.T., Kooyman, D.L., and Reynolds, P.R. (2017). Plausible Roles for RAGE in Conditions Exacerbated by Direct and Indirect (Secondhand) Smoke Exposure. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18030652"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"10595","DOI":"10.1093\/nar\/gkx705","article-title":"Homeostatic nuclear RAGE-ATM interaction is essential for efficient DNA repair","volume":"45","author":"Kumar","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1007\/s00441-017-2691-z","article-title":"Inhibition of the receptor for advanced glycation end-products (RAGE) protects from secondhand smoke (SHS)-induced intrauterine growth restriction IUGR in mice","volume":"370","author":"Lewis","year":"2017","journal-title":"Cell Tissue Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.jri.2011.02.004","article-title":"DNA damage and health in pregnancy","volume":"89","author":"Furness","year":"2011","journal-title":"J. Reprod. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1667\/0033-7587(2001)156[0347:VOFNSO]2.0.CO;2","article-title":"Visualization of focal nuclear sites of DNA repair synthesis induced by bleomycin in human cells","volume":"156","author":"Tomilin","year":"2001","journal-title":"Radiat. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1038\/sj.onc.1201862","article-title":"Agents that cause DNA double strand breaks lead to p16INK4a enriment and the premature senescence of normal fibroblasts","volume":"16","author":"Robles","year":"1998","journal-title":"Oncogene"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1093\/toxsci\/kfh061","article-title":"Genotoxic and antiapoptotic effect of nicotine on human gingival fibroblasts","volume":"79","author":"Argentin","year":"2004","journal-title":"Toxicol. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1095\/biolreprod.111.094797","article-title":"Placental TonEBP\/NFAT5 osmolyte regulation in an ovine model of intrauterine growth restriction","volume":"86","author":"Arroyo","year":"2012","journal-title":"Biol. Reprod."},{"key":"ref_25","first-page":"305","article-title":"Gamma-H2AX\u2014A novel biomarker for DNA double-strand breaks","volume":"22","author":"Kuo","year":"2008","journal-title":"In Vivo"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Tadesse, S., Kidane, D., Guller, S., Luo, T., Norwitz, N.G., Arcuri, F., Toti, P., and Norwitz, E.R. (2014). In vivo and in vitro evidence for placental DNA damage in preeclampsia. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0086791"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.humpath.2013.07.024","article-title":"Smoking during pregnancy causes double-strand DNA break damage to the placenta","volume":"45","author":"Slatter","year":"2014","journal-title":"Hum. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1007\/978-1-61779-998-3_40","article-title":"Histone H2AX phosphorylation: A marker for DNA damage","volume":"920","author":"Sharma","year":"2012","journal-title":"Methods Mol. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/leu.2010.6","article-title":"gammaH2AX: A sensitive molecular marker of DNA damage and repair","volume":"24","author":"Mah","year":"2010","journal-title":"Leukemia"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mrrev.2015.07.001","article-title":"Persistent gammaH2AX: A promising molecular marker of DNA damage and aging","volume":"766","author":"Siddiqui","year":"2015","journal-title":"Mutat. Res. Rev. Mutat. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1002\/1098-1128(200103)21:2<129::AID-MED1003>3.0.CO;2-H","article-title":"Inhibition of p38 mitogen-activated protein kinase provides neuroprotection in cerebral focal ischemia","volume":"21","author":"Barone","year":"2001","journal-title":"Med. Res. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2877","DOI":"10.3390\/biom5042877","article-title":"ATM-Dependent Phosphorylation of All Three Members of the MRN Complex: From Sensor to Adaptor","volume":"5","author":"Lavin","year":"2015","journal-title":"Biomolecules"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"7749","DOI":"10.1038\/sj.onc.1210880","article-title":"ATM and the Mre11 complex combine to recognize and signal DNA double-strand breaks","volume":"26","author":"Lavin","year":"2007","journal-title":"Oncogene"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5612","DOI":"10.1093\/emboj\/cdg541","article-title":"Requirement of the MRN complex for ATM activation by DNA damage","volume":"22","author":"Uziel","year":"2003","journal-title":"EMBO J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3682","DOI":"10.1016\/j.febslet.2010.07.029","article-title":"The MRN complex in double-strand break repair and telomere maintenance","volume":"584","author":"Lamarche","year":"2010","journal-title":"FEBS Lett."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/4\/857\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:27:30Z","timestamp":1760365650000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/4\/857"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,9]]},"references-count":35,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["cells10040857"],"URL":"https:\/\/doi.org\/10.3390\/cells10040857","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,9]]}}}