biostudies-literatureSanchez ACLehigh UniversityNational Institutes of HealthNIGMS NIH HHS501-513https://www.ebi.ac.uk/biostudies/studies/S-EPMC8942496biostudies-literatureUnknown21(5)Cornelia de Lange syndrome (CdLS) and Roberts syndrome (RBS) are severe developmental maladies that arise from mutation of cohesin (including <i>SMC3</i>, CdLS) and <i>ESCO2</i> (RBS). Though ESCO2 activates cohesin, CdLS and RBS etiologies are currently considered non-synonymous and for which pharmacological treatments are unavailable. Here, we identify a unifying mechanism that integrates these genetic maladies to pharmacologically-induced teratogenicity via thalidomide. Our results reveal that Esco2 and cohesin co-regulate the transcription of a component of CRL4 ubiquitin ligase through which thalidomide exerts teratogenic effects. These findings are the first to link RBS and CdLS to thalidomide teratogenicity and offer new insights into treatments.Cell cycle (Georgetown, Tex.)Esco2 and cohesin regulate CRL4 ubiquitin ligase <i>ddb1</i> expression and thalidomide teratogenicity.PMC8942496R15GM110631Faculty Research GrantR15 GM110631R15 GM139097Nemes Graduate Student Research FellowshipIovine MKSkibbens RVThren EDSanchez ACfalseEsco2 and cohesin regulate CRL4 ubiquitin ligase <i>ddb1</i> expression and thalidomide teratogenicity.Cornelia de Lange syndrome (CdLS) and Roberts syndrome (RBS) are severe developmental maladies that arise from mutation of cohesin (including <i>SMC3</i>, CdLS) and <i>ESCO2</i> (RBS). Though ESCO2 activates cohesin, CdLS and RBS etiologies are currently considered non-synonymous and for which pharmacological treatments are unavailable. Here, we identify a unifying mechanism that integrates these genetic maladies to pharmacologically-induced teratogenicity via thalidomide. Our results reveal that Esco2 and cohesin co-regulate the transcription of a component of CRL4 ubiquitin ligase through which thalidomide exerts teratogenic effects. These findings are the first to link RBS and CdLS to thalidomide teratogenicity and offer new insights into treatments.2022-01-01T00:00:00Z2022 Mar2025-04-04T08:53:53.385Z2025-04-04T08:53:53.385ZS-EPMC89424963498932210.1080/15384101.2021.2023304