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It is conceivable that Claspin gene (CLSPN) alterations may contribute to cancer development. Therefore, CLSPN germline alterations were characterized in sporadic and familial breast cancer and glioma samples, as well as in six cancer cell lines. Their association to cancer susceptibility and functional impact were investigated. Eight variants were identified (c.-68C&gt;T, c.17G&gt;A, c.1574A&gt;G, c.2230T&gt;C, c.2028+16G&gt;A, c.3595-3597del, and c.3839C&gt;T). CLSPN c.1574A&gt;G (p.Asn525Ser) was significantly associated with breast cancer and was shown to cause partial exon skipping and decreased Claspin expression and Chk1 activation in a minigene splicing assay and in signalling experiments, respectively. CLSPN c.2028+16G&gt;A was significantly associated with familial breast cancer and glioma, whereas c.2230T&gt;C (p.Ser744Pro), was exclusively detected in breast cancer and glioma patients, but not in healthy controls. The remaining variants lacked a significant association with cancer. Nevertheless, the c.-68C&gt;T promoter variant increased transcriptional activity in a luciferase assay. In conclusion, some of the CLSPN variants identified in the present study appear to modulate Claspin\u2019s function by altering CLSPN transcription and RNA processing, as well as Chk1 activation.<\/jats:p>","DOI":"10.3390\/cancers12092396","type":"journal-article","created":{"date-parts":[[2020,8,24]],"date-time":"2020-08-24T10:37:32Z","timestamp":1598265452000},"page":"2396","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Implications of CLSPN Variants in Cellular Function and Susceptibility to Cancer"],"prefix":"10.3390","volume":"12","author":[{"given":"Diana","family":"Azenha","sequence":"first","affiliation":[{"name":"Faculdade de Farm\u00e1cia da Universidade de Coimbra, 3000-548 Coimbra, Portugal"},{"name":"New preventive and therapeutic strategies, Centro de Neuroci\u00eancias e Biologia Celular, Universidade de Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Radiobiology, Department of Medical Physics, Instituto Portugu\u00eas de Oncologia de Coimbra de Francisco Gentil, 3000-651 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2702-3857","authenticated-orcid":false,"given":"Santiago","family":"Hernandez-Perez","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n, Hospital Universitario de Canarias, 38320 Tenerife, Spain"}]},{"given":"Yuse","family":"Martin","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n, Hospital Universitario de Canarias, 38320 Tenerife, Spain"}]},{"given":"Marta S.","family":"Viegas","sequence":"additional","affiliation":[{"name":"New preventive and therapeutic strategies, Centro de Neuroci\u00eancias e Biologia Celular, Universidade de Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Molecular Pathology Laboratory, Instituto Portugu\u00eas de Oncologia de Coimbra de Francisco Gentil, 3000-651 Coimbra, Portugal"}]},{"given":"Alexandra","family":"Martins","sequence":"additional","affiliation":[{"name":"Inserm U1245, UNIROUEN, Normandie Univ, Normandy Centre for Genomic and Personalized Medicine, 76183 Rouen, France"}]},{"given":"Maria C.","family":"Lopes","sequence":"additional","affiliation":[{"name":"Faculdade de Farm\u00e1cia da Universidade de Coimbra, 3000-548 Coimbra, Portugal"},{"name":"New preventive and therapeutic strategies, Centro de Neuroci\u00eancias e Biologia Celular, Universidade de Coimbra, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1274-3576","authenticated-orcid":false,"given":"Eric W. -F.","family":"Lam","sequence":"additional","affiliation":[{"name":"Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London W12 0NN, UK"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4473-8894","authenticated-orcid":false,"given":"Raimundo","family":"Freire","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n, Hospital Universitario de Canarias, 38320 Tenerife, Spain"},{"name":"Instituto de Tecnolog\u00edas Biom\u00e9dicas, Universidad de La Laguna, 38200 Tenerife, Spain"},{"name":"Universidad Fernando Pessoa Canarias, 35450 Las Palmas de Gran Canaria, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4271-2869","authenticated-orcid":false,"given":"Teresa C.","family":"Martins","sequence":"additional","affiliation":[{"name":"New preventive and therapeutic strategies, Centro de Neuroci\u00eancias e Biologia Celular, Universidade de Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Radiobiology, Department of Medical Physics, Instituto Portugu\u00eas de Oncologia de Coimbra de Francisco Gentil, 3000-651 Coimbra, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0092-8674(00)81683-9","article-title":"The hallmarks of cancer","volume":"100","author":"Hanahan","year":"2000","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of Cancer: The Next Generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1146\/annurev-pathol-012615-044446","article-title":"Mechanisms and Consequences of Cancer Genome Instability: Lessons from Genome Sequencing Studies","volume":"11","author":"Lee","year":"2016","journal-title":"Annu. 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