{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T18:02:20Z","timestamp":1787162540962,"version":"build-2736575974"},"reference-count":52,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2024,12,7]],"date-time":"2024-12-07T00:00:00Z","timestamp":1733529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Associazione Italiana per la Ricerca sul Cancro","award":["IG23284"],"award-info":[{"award-number":["IG23284"]}]},{"name":"Associazione Italiana per la Ricerca sul Cancro","award":["FOE-2021 DBA.AD005.225"],"award-info":[{"award-number":["FOE-2021 DBA.AD005.225"]}]},{"name":"CNR project","award":["IG23284"],"award-info":[{"award-number":["IG23284"]}]},{"name":"CNR project","award":["FOE-2021 DBA.AD005.225"],"award-info":[{"award-number":["FOE-2021 DBA.AD005.225"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Cornelia de Lange syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder. Pathogenic variants in genes encoding the structural subunits and regulatory proteins of the cohesin complex (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the primary contributors to the pathogenesis of CdLS. Pathogenic variations in these genes disrupt normal cohesin function, leading to the syndrome\u2019s diverse and complex clinical presentation. In this study, we discovered that cells harboring variants in the NIPBL, SMC1A and HDAC8 genes exhibit spontaneous genome instability, elevated oxidative stress and premature cellular aging. These findings suggest that cohesin plays a critical role in maintaining proper cellular function and highlight its contribution to the pathophysiology seen in the related diagnoses.<\/jats:p>","DOI":"10.3390\/cells13232025","type":"journal-article","created":{"date-parts":[[2024,12,9]],"date-time":"2024-12-09T06:16:14Z","timestamp":1733724974000},"page":"2025","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Genome Instability and Senescence Are Markers of Cornelia de Lange Syndrome Cells"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1481-2101","authenticated-orcid":false,"given":"Maddalena","family":"Di Nardo","sequence":"first","affiliation":[{"name":"Institute for Biomedical Technologies, National Research Council, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian D.","family":"Krantz","sequence":"additional","affiliation":[{"name":"Roberts Individualized Medical Genetics Center, Division of Human Genetics, The Department of Pediatrics, The Children\u2019s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104-4318, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7701-6543","authenticated-orcid":false,"given":"Antonio","family":"Musio","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Technologies, National Research Council, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1146\/annurev-genet-112618-043633","article-title":"Organization of Chromosomal DNA by SMC Complexes","volume":"53","author":"Yatskevich","year":"2019","journal-title":"Annu. Rev. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.ceb.2018.11.006","article-title":"Cohesion and cohesin-dependent chromatin organization","volume":"58","author":"Nishiyama","year":"2019","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1111\/febs.16362","article-title":"Full circle: A brief history of cohesin and the regulation of gene expression","volume":"290","author":"Horsfield","year":"2022","journal-title":"FEBS J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1186\/s13046-022-02321-5","article-title":"The multifaceted roles of cohesin in cancer","volume":"41","author":"Pallotta","year":"2022","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.tig.2018.03.003","article-title":"SMC Complexes: Universal DNA Looping Machines with Distinct Regulators","volume":"34","author":"Rowland","year":"2018","journal-title":"Trends Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/nature12634","article-title":"Mutational landscape and significance across 12 major cancer types","volume":"502","author":"Kandoth","year":"2013","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1038\/nature12912","article-title":"Discovery and saturation analysis of cancer genes across 21 tumour types","volume":"505","author":"Lawrence","year":"2014","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/ng.3168","article-title":"Pan-cancer network analysis identifies combinations of rare somatic mutations across pathways and protein complexes","volume":"47","author":"Leiserson","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s13046-021-01858-1","article-title":"ESCO2 promotes lung adenocarcinoma progression by regulating hnRNPA1 acetylation","volume":"40","author":"Zhu","year":"2021","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1038\/ng.2800","article-title":"Frequent truncating mutations of STAG2 in bladder cancer","volume":"45","author":"Solomon","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1158\/2159-8290.CD-13-1037","article-title":"The genomic landscape of pediatric Ewing sarcoma","volume":"4","author":"Crompton","year":"2014","journal-title":"Cancer Discov."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1158\/2159-8290.CD-14-0622","article-title":"Genomic landscape of Ewing sarcoma defines an aggressive subtype with co-association of STAG2 and TP53 mutations","volume":"4","author":"Tirode","year":"2014","journal-title":"Cancer Discov."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1016\/j.cell.2013.09.034","article-title":"The somatic genomic landscape of glioblastoma","volume":"155","author":"Brennan","year":"2013","journal-title":"Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1038\/ng.2731","article-title":"Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms","volume":"45","author":"Kon","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1186\/s13046-024-02976-2","article-title":"The synergism of SMC1A cohesin gene silencing and bevacizumab against colorectal cancer","volume":"43","author":"Astigiano","year":"2024","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1159\/000448747","article-title":"Disorders of Transcriptional Regulation: An Emerging Category of Multiple Malformation Syndromes","volume":"7","author":"Izumi","year":"2016","journal-title":"Mol. Syndr. Syndromol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1038\/s41576-018-0031-0","article-title":"Diagnosis and management of Cornelia de Lange syndrome: First international consensus statement","volume":"19","author":"Kline","year":"2018","journal-title":"Nat. Rev. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1016\/j.ajhg.2012.04.019","article-title":"RAD21 mutations cause a human cohesinopathy","volume":"90","author":"Deardorff","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1086\/511888","article-title":"Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of cornelia de Lange syndrome with predominant mental retardation","volume":"80","author":"Deardorff","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1038\/nature11316","article-title":"HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle","volume":"489","author":"Deardorff","year":"2012","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1038\/ng1363","article-title":"NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome","volume":"36","author":"Tonkin","year":"2004","journal-title":"Nat. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"eadl4239","DOI":"10.1126\/sciadv.adl4239","article-title":"Gastrulation-stage gene expression in Nipbl (+\/\u2212) mouse embryos foreshadows the development of syndromic birth defects","volume":"10","author":"Chea","year":"2024","journal-title":"Sci. Adv."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Muto, A., Calof, A.L., Lander, A.D., and Schilling, T.F. (2011). Multifactorial Origins of Heart and Gut Defects in nipbl-Deficient Zebrafish, a Model of Cornelia de Lange Syndrome. PLoS Biol., 9.","DOI":"10.1371\/journal.pbio.1001181"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Kawauchi, S., Calof, A.L., Santos, R., Lopez-Burks, M.E., Young, C.M., Hoang, M.P., Chua, A., Lao, T., Lechner, M.S., and Daniel, J.A. (2009). Multiple organ system defects and transcriptional dysregulation in the Nipbl(+\/-) mouse, a model of Cornelia de Lange Syndrome. PLoS Genet., 5.","DOI":"10.1371\/journal.pgen.1000650"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Liu, J., Zhang, Z., Bando, M., Itoh, T., Deardorff, M.A., Clark, D., Kaur, M., Tandy, S., Kondoh, T., and Rappaport, E. (2009). Transcriptional dysregulation in NIPBL and cohesin mutant human cells. PLoS Biol., 7.","DOI":"10.1371\/journal.pbio.1000119"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Gimenez, G., Kalev-Zylinska, M.L., Morison, I., Bohlander, S.K., Horsfield, J.A., and Antony, J. (2024). Cohesin rad21 mutation dysregulates erythropoiesis and granulopoiesis output within the whole kidney marrow of adult zebrafish. Am. J. Physiol. Cell Physiol.","DOI":"10.1152\/ajpcell.00657.2024"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4551","DOI":"10.1038\/s41467-021-24808-z","article-title":"Disruption of NIPBL\/Scc2 in Cornelia de Lange Syndrome provokes cohesin genome-wide redistribution with an impact in the transcriptome","volume":"12","author":"Garcia","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3127","DOI":"10.1038\/s41467-021-23500-6","article-title":"Cornelia de Lange syndrome-associated mutations cause a DNA damage signalling and repair defect","volume":"12","author":"Olley","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1093\/hmg\/ddm098","article-title":"Increased DNA damage sensitivity of Cornelia de Lange syndrome cells: Evidence for impaired recombinational repair","volume":"16","author":"Vrouwe","year":"2007","journal-title":"Hum. Mol. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Di Nardo, M., and Musio, A. (2024). Cohesin\u2014Bridging the gap among gene transcription, genome stability, and human diseases. FEBS Lett., 598.","DOI":"10.1002\/1873-3468.14949"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1093\/hmg\/ddn369","article-title":"Cornelia de Lange syndrome mutations in SMC1A or SMC3 affect binding to DNA","volume":"18","author":"Revenkova","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1002\/ajmg.a.61539","article-title":"Whole-genome sequencing reveals complex chromosome rearrangement disrupting NIPBL in infant with Cornelia de Lange syndrome","volume":"182","author":"Pettersson","year":"2020","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Gervasini, C., Picinelli, C., Azzollini, J., Rusconi, D., Masciadri, M., Cereda, A., Marzocchi, C., Zampino, G., Selicorni, A., and Tenconi, R. (2013). Genomic imbalances in patients with a clinical presentation in the spectrum of Cornelia de Lange syndrome. BMC Med. Genet., 14.","DOI":"10.1186\/1471-2350-14-41"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3002","DOI":"10.1093\/hmg\/ddy203","article-title":"Antioxidant treatment ameliorates phenotypic features of SMC1A-mutated Cornelia de Lange syndrome in vitro and in vivo","volume":"27","author":"Cukrov","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref_35","first-page":"1","article-title":"An International System for Human Cytogenetic Nomenclature (1985) ISCN 1985. Report of the Standing Committee on Human Cytogenetic Nomenclature","volume":"21","author":"Harnden","year":"1985","journal-title":"Birth Defects Orig. Artic. Ser."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1002\/ajmg.c.30137","article-title":"Natural history of aging in Cornelia de Lange syndrome","volume":"145","author":"Kline","year":"2007","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2113","DOI":"10.1002\/ajmg.a.63247","article-title":"Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, genotype-phenotype correlations and common mechanisms","volume":"191","author":"Kaur","year":"2023","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6111","DOI":"10.1021\/pr300760p","article-title":"Proteomic profile identifies dysregulated pathways in Cornelia de Lange syndrome cells with distinct mutations in SMC1A and SMC3 genes","volume":"11","author":"Gimigliano","year":"2012","journal-title":"J. Proteome Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1016\/j.molcel.2004.11.026","article-title":"Postreplicative recruitment of cohesin to double-strand breaks is required for DNA repair","volume":"16","author":"Strom","year":"2004","journal-title":"Mol. Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1016\/j.molcel.2004.11.027","article-title":"DNA damage response pathway uses histone modification to assemble a double-strand break-specific cohesin domain","volume":"16","author":"Unal","year":"2004","journal-title":"Mol. Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1186\/s12967-015-0503-3","article-title":"Enhanced expression of cohesin loading factor NIPBL confers poor prognosis and chemotherapy resistance in non-small cell lung cancer","volume":"13","author":"Xu","year":"2015","journal-title":"J. Transl. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/j.molcel.2010.08.008","article-title":"An Smc3 acetylation cycle is essential for establishment of sister chromatid cohesion","volume":"39","author":"Beckouet","year":"2010","journal-title":"Mol. Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1101\/gad.1200304","article-title":"Phosphorylation of SMC1 is a critical downstream event in the ATM-NBS1-BRCA1 pathway","volume":"18","author":"Kitagawa","year":"2004","journal-title":"Genes. Dev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1101\/gad.970702","article-title":"SMC1 is a downstream effector in the ATM\/NBS1 branch of the human S-phase checkpoint","volume":"16","author":"Yazdi","year":"2002","journal-title":"Genes. Dev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1101\/gad.970602","article-title":"Involvement of the cohesin protein, Smc1, in Atm-dependent and independent responses to DNA damage","volume":"16","author":"Kim","year":"2002","journal-title":"Genes. Dev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3443","DOI":"10.1073\/pnas.0712384105","article-title":"Chromatid cohesion defects may underlie chromosome instability in human colorectal cancers","volume":"105","author":"Barber","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1093\/hmg\/ddu394","article-title":"Mutant cohesin drives chromosomal instability in early colorectal adenomas","volume":"23","author":"Cucco","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Pallotta, M.M., Di Nardo, M., and Musio, A. (2024). Synthetic Lethality between Cohesin and WNT Signaling Pathways in Diverse Cancer Contexts. Cells, 13.","DOI":"10.3390\/cells13070608"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1186\/s13046-019-1116-0","article-title":"Overexpression of the cohesin-core subunit SMC1A contributes to colorectal cancer development","volume":"38","author":"Sarogni","year":"2019","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1002\/ajmg.a.62992","article-title":"Cornelia de Lange syndrome and cancer: An open question","volume":"191","author":"Pallotta","year":"2023","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_51","unstructured":"Adam, M.P., Feldman, J., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Gripp, K.W., and Amemiya, A. (1993). Fanconi Anemia. GeneReviews((R)), University of Washington."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.devcel.2020.05.025","article-title":"Persistent DNA Damage and Senescence in the Placenta Impacts Developmental Outcomes of Embryos","volume":"54","author":"Singh","year":"2020","journal-title":"Dev. Cell"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/23\/2025\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:49:33Z","timestamp":1760114973000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/23\/2025"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,7]]},"references-count":52,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["cells13232025"],"URL":"https:\/\/doi.org\/10.3390\/cells13232025","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,7]]}}}