{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T05:03:38Z","timestamp":1772168618977,"version":"3.50.1"},"reference-count":51,"publisher":"The Company of Biologists","issue":"10","license":[{"start":{"date-parts":[[2021,2,8]],"date-time":"2021-02-08T00:00:00Z","timestamp":1612742400000},"content-version":"vor","delay-in-days":496,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100002426","name":"Fondazione Telethon","doi-asserted-by":"publisher","award":["GEP15050"],"award-info":[{"award-number":["GEP15050"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fondazione Terzo Pilastro Internazionale"},{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["AIRC IG15410"],"award-info":[{"award-number":["AIRC IG15410"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Istituto Italiano di Tecnologia Sapienza University of Rome"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,10,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Schimke immuno-osseous dysplasia is an autosomal recessive genetic osteochondrodysplasia characterized by dysmorphism, spondyloepiphyseal dysplasia, nephrotic syndrome and frequently T cell immunodeficiency. Several hypotheses have been proposed to explain the pathophysiology of the disease; however, the mechanism by which SMARCAL1 mutations cause the syndrome is elusive. Here, we generated a conditional SMARCAL1 knockdown model in induced pluripotent stem cells (iPSCs) to mimic conditions associated with the severe form the disease. Using multiple cellular endpoints, we characterized this model for the presence of phenotypes linked to the replication caretaker role of SMARCAL1. Our data show that conditional knockdown of SMARCAL1 in human iPSCs induces replication-dependent and chronic accumulation of DNA damage triggering the DNA damage response. Furthermore, they indicate that accumulation of DNA damage and activation of the DNA damage response correlates with increased levels of R-loops and replication-transcription interference. Finally, we provide evidence that SMARCAL1-deficient iPSCs maintain active DNA damage response beyond differentiation, possibly contributing to the observed altered expression of a subset of germ layer-specific master genes. Confirming the relevance of SMARCAL1 loss for the observed phenotypes, they are prevented or rescued after re-expression of wild-type SMARCAL1 in our iPSC model. In conclusion, our conditional SMARCAL1 knockdown model in iPSCs may represent a powerful model when studying pathogenetic mechanisms of severe Schimke immuno-osseous dysplasia.<\/jats:p>","DOI":"10.1242\/dmm.039487","type":"journal-article","created":{"date-parts":[[2019,9,12]],"date-time":"2019-09-12T15:25:17Z","timestamp":1568301917000},"source":"Crossref","is-referenced-by-count":13,"title":["Inducible SMARCAL1 knockdown in iPSC reveals a link between replication stress and altered expression of master differentiation genes"],"prefix":"10.1242","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9473-4982","authenticated-orcid":false,"given":"Giusj Monia","family":"Pugliese","sequence":"first","affiliation":[{"name":"Istituto Superiore di Sanit\u00e0 1 Mechanisms, Biomarkers and Models Unit, Department of Environment and Health , , , 00161 Rome , Italy"},{"name":"Viale Regina Elena 299 1 Mechanisms, Biomarkers and Models Unit, Department of Environment and Health , , , 00161 Rome , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federico","family":"Salaris","sequence":"additional","affiliation":[{"name":"Center for Life Nano Science, Istituto Italiano di Tecnologia 2 , Viale Regina Elena 291, 00161 Rome , Italy"},{"name":"Sapienza University of Rome 3 Department of Biology and Biotechnology Charles Darwin , , P.le A. Moro 5, 00185 Rome , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6967-4941","authenticated-orcid":false,"given":"Valentina","family":"Palermo","sequence":"additional","affiliation":[{"name":"Istituto Superiore di Sanit\u00e0 1 Mechanisms, Biomarkers and Models Unit, Department of Environment and Health , , , 00161 Rome , Italy"},{"name":"Viale Regina Elena 299 1 Mechanisms, Biomarkers and Models Unit, Department of Environment and Health , , , 00161 Rome , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5941-9656","authenticated-orcid":false,"given":"Veronica","family":"Marabitti","sequence":"additional","affiliation":[{"name":"Istituto Superiore di Sanit\u00e0 1 Mechanisms, Biomarkers and Models Unit, Department of Environment and Health , , , 00161 Rome , Italy"},{"name":"Viale Regina Elena 299 1 Mechanisms, Biomarkers and Models Unit, Department of Environment and Health , , , 00161 Rome , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicol\u00f2","family":"Morina","sequence":"additional","affiliation":[{"name":"Istituto Superiore di Sanit\u00e0 1 Mechanisms, Biomarkers and Models Unit, Department of Environment and Health , , , 00161 Rome , Italy"},{"name":"Viale Regina Elena 299 1 Mechanisms, Biomarkers and Models Unit, Department of Environment and Health , , , 00161 Rome , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9999-7223","authenticated-orcid":false,"given":"Alessandro","family":"Rosa","sequence":"additional","affiliation":[{"name":"Center for Life Nano Science, Istituto Italiano di Tecnologia 2 , Viale Regina Elena 291, 00161 Rome , Italy"},{"name":"Sapienza University of Rome 3 Department of Biology and Biotechnology Charles Darwin , , P.le A. Moro 5, 00185 Rome , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annapaola","family":"Franchitto","sequence":"additional","affiliation":[{"name":"Istituto Superiore di Sanit\u00e0 1 Mechanisms, Biomarkers and Models Unit, Department of Environment and Health , , , 00161 Rome , Italy"},{"name":"Viale Regina Elena 299 1 Mechanisms, Biomarkers and Models Unit, Department of Environment and Health , , , 00161 Rome , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2702-3523","authenticated-orcid":false,"given":"Pietro","family":"Pichierri","sequence":"additional","affiliation":[{"name":"Istituto Superiore di Sanit\u00e0 1 Mechanisms, Biomarkers and Models Unit, Department of Environment and Health , , , 00161 Rome , Italy"},{"name":"Viale Regina Elena 299 1 Mechanisms, Biomarkers and Models Unit, Department of Environment and Health , , , 00161 Rome , Italy"},{"name":"Istituto Nazionale Biostrutture e Biosistemi 4 , Via delle Medaglie d'Oro, 00136 Rome , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2019,10,17]]},"reference":[{"key":"2024061302145801600_DMM039487C1","doi-asserted-by":"publisher","first-page":"10660","DOI":"10.1038\/ncomms10660","article-title":"A short G1 phase imposes constitutive replication stress and fork remodelling in mouse embryonic stem cells","volume":"7","author":"Ahuja","year":"2016","journal-title":"Nat. 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