{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:44:46Z","timestamp":1760060686909,"version":"build-2065373602"},"reference-count":141,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T00:00:00Z","timestamp":1757462400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cancer cells arise from the cumulative acquisition of genetic and epigenetic alterations that affect vital cellular functions. Genomic instability results from deficiencies in protective mechanisms, such as cell cycle checkpoints, DNA replication control, or DNA repair. Claspin integrates a group of crucial proteins that maintain genome integrity. It participates in key cellular events such as DNA damage checkpoint activation, DNA replication, replication stress responses, DNA repair, epigenetic memory, and apoptosis. Given its crucial functions, a role for Claspin in cancer is not a surprise. Indeed, there is a considerable body of evidence linking Claspin deregulation with cancer. For instance, over-expression of Claspin and Tim promoted the survival of cancer cells by enabling adaptation to oncogene-induced replication stress. In addition, Claspin gene (CLSPN) mutations that affect checkpoint regulation have been identified in cancer patients, suggesting that they may contribute to cancer development. Changes in Claspin expression levels may be used as a prognostic marker in several types of cancer. Finally, several therapy-resistance signaling pathways seem to converge onto Claspin\u2019s stabilization, turning Claspin into an attractive target for chemo- and radio-sensitization. In this review, we will focus on the role of Claspin in cancer and ways in which Claspin can be exploited in cancer therapy.<\/jats:p>","DOI":"10.3390\/ijms26188828","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T14:14:55Z","timestamp":1757513695000},"page":"8828","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Claspin and Cancer: Where Are We Now?"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2612-9975","authenticated-orcid":false,"given":"Diana","family":"Azenha","sequence":"first","affiliation":[{"name":"Faculdade de Farm\u00e1cia da Universidade de Coimbra, P\u00f3lo das Ci\u00eancias da Sa\u00fade, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal"}]},{"given":"Teresa C.","family":"Martins","sequence":"additional","affiliation":[{"name":"Innovative Therapies: Tumor Microenvironment and Targeted Therapies, Center for Neuroscience and Cell Biology, Faculdade de Medicina, University of Coimbra, Rua Larga, P\u00f3lo I, 1\u00ba andar, 3004-504 Coimbra, Portugal"},{"name":"Molecular Pathology Laboratory, Portuguese Institute for Oncology at Coimbra Francisco Gentil, EPE, Av. Bissaya Barreto, 98, Apartado 2005, 3000-651 Coimbra, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,10]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1158\/2159-8290.CD-21-1059","article-title":"Hallmarks of cancer: New dimensions","volume":"12","author":"Hanahan","year":"2022","journal-title":"Cancer Discov."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1042\/BJ20112100","article-title":"Replication fork dynamics and the DNA damage response","volume":"443","author":"Jones","year":"2012","journal-title":"Biochem. J."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Atemin, A., Ivanona, A., Kanev, P.-B., Uzunova, S., Nedelcheva-Veleva, M., and Stoynov, S. (2024). Dynamics of replication-associated protein levels through the cell cycle. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25158230"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/S1097-2765(05)00092-4","article-title":"Claspin, a novel protein required for the activation of Chk1 during a DNA replication checkpoint response in Xenopus egg extracts","volume":"6","author":"Kumagai","year":"2000","journal-title":"Mol. Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.dnarep.2017.09.002","article-title":"Claspin functions in cell homeostasis\u2014A link to cancer?","volume":"59","author":"Azenha","year":"2017","journal-title":"DNA Repair"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"35337","DOI":"10.1074\/jbc.M506460200","article-title":"Cleavage of claspin by caspase-7 during apoptosis inhibits the Chk1 pathway","volume":"280","author":"Clarke","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1038\/sj.cdd.4402134","article-title":"Cleavage and degradation of Claspin during apoptosis by caspases and the proteasome","volume":"14","author":"Semple","year":"2007","journal-title":"Cell Death Differ."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1007\/s00294-017-0690-y","article-title":"Mrc1\/Claspin: A new role for regulation of origin firing","volume":"63","author":"Masai","year":"2017","journal-title":"Curr. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"332","DOI":"10.4161\/cc.23177","article-title":"Separation of intra-S checkpoint protein contributions to DNA replication fork protection and genomic stability in normal human fibroblasts","volume":"12","author":"Patel","year":"2013","journal-title":"Cell Cycle"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5029","DOI":"10.1016\/j.cell.2024.07.017","article-title":"The fork protection complex promotes parental histone recycling and epigenetic memory","volume":"187","author":"Charlton","year":"2024","journal-title":"Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3681","DOI":"10.1111\/febs.13387","article-title":"DNA damage control: Regulation and functions of checkpoint kinase 1","volume":"282","author":"Smits","year":"2015","journal-title":"FEBS J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"30057","DOI":"10.1074\/jbc.M301136200","article-title":"Human claspin is required for replication checkpoint control","volume":"278","author":"Chini","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2115","DOI":"10.1042\/BCJ20220101","article-title":"Claspin haploinsufficiency leads to defects in fertility, hyperplasia and an increased oncogenic potential","volume":"479","author":"Madgwick","year":"2022","journal-title":"Biochem. J."},{"key":"ref_15","first-page":"185","article-title":"Generation and analysis of Brca1 conditional knockout mice","volume":"280","author":"Deng","year":"2004","journal-title":"Methods Mol. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s10555-012-9403-7","article-title":"Mouse models of BRCA1 and their application to breast cancer research","volume":"32","author":"Dine","year":"2013","journal-title":"Cancer Metastasis Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.1101\/gad.14.12.1448","article-title":"Chk1 is an essential kinase that is regulated by Atr and required for the G(2)\/M DNA damage checkpoint","volume":"14","author":"Liu","year":"2000","journal-title":"Genes Dev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1101\/gad.14.12.1439","article-title":"Aberrant cell cycle checkpoint function and early embryonic death in Chk1(\u2212\/\u2212) mice","volume":"14","author":"Takai","year":"2000","journal-title":"Genes Dev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1007\/s00412-013-0411-3","article-title":"DNA replication and homologous recombination factors: Acting together to maintain genome stability","volume":"122","author":"Aze","year":"2013","journal-title":"Chromosoma"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e108819","DOI":"10.15252\/embj.2021108819","article-title":"Structure of a human replisome shows the organization and interactions of a DNA replication machine","volume":"40","author":"Jones","year":"2021","journal-title":"Embo J."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Pellegrini, L. (2023). The CMG DNA helicase and the core replisome. Curr. Opin. Struct. Biol., 81.","DOI":"10.1016\/j.sbi.2023.102612"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2373","DOI":"10.1091\/mbc.e07-10-1035","article-title":"Claspin promotes normal replication fork rates in human cells","volume":"19","author":"Petermann","year":"2008","journal-title":"Mol. Biol. Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1093\/hmg\/ddm340","article-title":"Loss of CHK1 function impedes DNA damage-induced FANCD2 monoubiquitination but normalizes the abnormal G2 arrest in Fanconi anemia","volume":"17","author":"Guervilly","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5974","DOI":"10.1074\/jbc.M109.076109","article-title":"Interactions of human mismatch repair proteins MutS\u03b1 and MutL\u03b1 with proteins of the ATR-Chk1 pathway","volume":"285","author":"Liu","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1016\/j.dnarep.2006.11.009","article-title":"Role of Claspin in regulation of nucleotide excision repair factor DDB2","volume":"6","author":"Wang","year":"2007","journal-title":"DNA Repair"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.molcel.2006.06.016","article-title":"Destruction of claspin by SCF\u03b2TrCP restrains Chk1 activation and facilitates recovery from genotoxic stress","volume":"23","author":"Mailand","year":"2006","journal-title":"Mol. Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1950","DOI":"10.1016\/j.cub.2006.08.026","article-title":"Polo-like kinase-1 controls proteasome-dependent degradation of claspin during checkpoint recovery","volume":"16","author":"Mamely","year":"2006","journal-title":"Curr. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.molcel.2006.06.013","article-title":"SCF\u03b2TrCP-mediated degradation of claspin regulates recovery from the DNA replication checkpoint response","volume":"23","author":"Peschiaroli","year":"2006","journal-title":"Mol. Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4176","DOI":"10.1016\/j.febslet.2006.06.071","article-title":"Regulation of Claspin degradation by the ubiquitin-proteasome pathway during the cell cycle and in response to ATR-dependent checkpoint activation","volume":"580","author":"Bennett","year":"2006","journal-title":"FEBS Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1083\/jcb.200807137","article-title":"USP7 counteracts SCF\u03b2TrCP- but not APC\/Cdh1-mediated proteolysis of Claspin","volume":"184","author":"Faustrup","year":"2009","journal-title":"J. Cell Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1038\/onc.2014.38","article-title":"USP29 controls the stability of checkpoint adaptor Claspin by deubiquitination","volume":"34","author":"Cabrera","year":"2015","journal-title":"Oncogene"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2384","DOI":"10.1158\/0008-5472.CAN-15-2890","article-title":"The deubiquitinase USP9X maintains DNA replication fork stability and DNA damage checkpoint responses by regulating CLASPIN during S-phase","volume":"76","author":"McGarry","year":"2016","journal-title":"Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.cell.2006.06.039","article-title":"A role for the deubiquitinating enzyme USP28 in control of the DNA-damage response","volume":"126","author":"Zhang","year":"2006","journal-title":"Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3245","DOI":"10.1038\/s41388-020-1220-9","article-title":"Posttranscriptional control of the RS response via TTP-mediated Claspin mRNA stabilization","volume":"39","author":"Lee","year":"2020","journal-title":"Oncogene"},{"key":"ref_35","first-page":"4255","article-title":"ATM and ATR signaling at a glance","volume":"128","author":"Awasthi","year":"2015","journal-title":"J. Cell Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/cr.2014.147","article-title":"RPA-coated single-stranded DNA as a platform for post-translational modifications in the DNA damage response","volume":"25","author":"Marechal","year":"2015","journal-title":"Cell Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e2","DOI":"10.1017\/erm.2020.3","article-title":"DNA damage checkpoint kinases in cancer","volume":"22","author":"Smith","year":"2020","journal-title":"Expert Rev. Mol. Med."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Marechal, A., and Zou, L. (2013). DNA damage sensing by the ATM and ATR kinases. Cold Spring Harb. Perspect. Biol., 5.","DOI":"10.1101\/cshperspect.a012716"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.mrrev.2014.10.003","article-title":"The fork and the kinase: A DNA replication tale from a CHK1 perspective","volume":"763","author":"Gottifredi","year":"2015","journal-title":"Mutat. Res.\/Rev. Mutat. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1042\/BJ20041966","article-title":"DNA-dependent phosphorylation of Chk1 and Claspin in a human cell-free system","volume":"388","author":"Clarke","year":"2005","journal-title":"Biochem. J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"6484","DOI":"10.1073\/pnas.0401847101","article-title":"Human Claspin works with BRCA1 to both positively and negatively regulate cell proliferation","volume":"101","author":"Lin","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1101\/gad.1398806","article-title":"Site-specific phosphorylation of a checkpoint mediator protein controls its responses to different DNA structures","volume":"20","author":"Yoo","year":"2006","journal-title":"Genes Dev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/bs.apcsb.2018.10.007","article-title":"Claspin: From replication stress and DNA damage responses to cancer therapy","volume":"115","author":"Azenha","year":"2019","journal-title":"Adv. Protein Chem. Struct. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3977","DOI":"10.1038\/onc.2008.17","article-title":"The checkpoint kinases Chk1 and Chk2 regulate the functional associations between hBRCA2 and Rad51 in response to DNA damage","volume":"27","author":"Bahassi","year":"2008","journal-title":"Oncogene"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1038\/ncb1212","article-title":"The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair","volume":"7","author":"Hansen","year":"2005","journal-title":"Nat. Cell Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1016\/j.cub.2012.07.034","article-title":"A DNA-damage selective role for BRCA1 E3 ligase in Claspin ubiquitylation, CHK1 activation, and DNA repair","volume":"22","author":"Sato","year":"2012","journal-title":"Curr. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/S0092-8674(04)00417-9","article-title":"Adaptation of a DNA replication checkpoint response depends upon inactivation of Claspin by the Polo-like kinase","volume":"117","author":"Yoo","year":"2004","journal-title":"Cell"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"10253","DOI":"10.1158\/0008-5472.CAN-06-2144","article-title":"Adaptation to the ionizing radiation-induced G2 checkpoint occurs in human cells and depends on checkpoint kinase 1 and Polo-like kinase 1 kinases","volume":"66","author":"Jensen","year":"2006","journal-title":"Cancer Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.4161\/cc.8.7.8040","article-title":"Claspin and Chk1 regulate replication fork stability by different mechanisms","volume":"8","author":"Scorah","year":"2009","journal-title":"Cell Cycle"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"5269","DOI":"10.1091\/mbc.e05-07-0671","article-title":"Roles of replication fork-interacting and Chk1-activating domains from Claspin in a DNA replication checkpoint response","volume":"16","author":"Lee","year":"2005","journal-title":"Mol. Biol. Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1111\/j.1365-2443.2011.01535.x","article-title":"Efficient expression and purification of human replication fork-stabilizing factor, Claspin, from mammalian cells: DNA-binding activity and novel protein interactions","volume":"16","author":"Uno","year":"2011","journal-title":"Genes Cells"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"39289","DOI":"10.1074\/jbc.M405793200","article-title":"Human Claspin is a ring-shaped DNA-binding protein with high affinity to branched DNA structures","volume":"279","author":"Sar","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"4888","DOI":"10.1111\/febs.12465","article-title":"Cell cycle-dependent formation of Cdc45-Claspin complexes in human cells is compromised by UV-mediated DNA damage","volume":"280","author":"Broderick","year":"2013","journal-title":"FEBS J."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"6907","DOI":"10.1096\/fj.201901926R","article-title":"OZF is a Claspin-interacting protein essential to maintain the replication fork progression rate under RS","volume":"34","author":"Feu","year":"2020","journal-title":"FASEB J."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"12135","DOI":"10.1038\/ncomms12135","article-title":"Claspin recruits Cdc7 kinase for initiation of DNA replication in human cells","volume":"7","author":"Yang","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.4161\/cc.10.10.15613","article-title":"Timeless functions independently of the Tim-Tipin complex to promote sister chromatid cohesion in normal human fibroblasts","volume":"10","author":"Patel","year":"2011","journal-title":"Cell Cycle"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.1128\/MCB.06727-11","article-title":"Altered replication in human cells promotes DMPK (CTG)(n) (CAG)(n) repeat instability","volume":"32","author":"Liu","year":"2012","journal-title":"Mol. Cell. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1101\/gad.1632808","article-title":"Chk1 and Claspin potentiate PCNA ubiquitination","volume":"22","author":"Yang","year":"2008","journal-title":"Genes Dev."},{"key":"ref_59","first-page":"1083","article-title":"Claspin inhibition leads to fragile site expression","volume":"48","author":"Focarelli","year":"2009","journal-title":"Genes Chrom. Canc."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"326","DOI":"10.2174\/138920210791616699","article-title":"DNA instability at chromosomal fragile sites in cancer","volume":"11","author":"Dillon","year":"2010","journal-title":"Curr. Genom."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1016\/S0092-8674(02)01113-3","article-title":"ATR regulates fragile site stability","volume":"111","author":"Casper","year":"2002","journal-title":"Cell"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"4381","DOI":"10.1038\/sj.onc.1209466","article-title":"Depletion of CHK1, but not CHK2, induces chromosomal instability and breaks at common fragile sites","volume":"25","author":"Durkin","year":"2006","journal-title":"Oncogene"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Koundrioukoff, S., Carignon, S., Techer, H., Letessier, A., Brison, O., and Debatisse, M. (2013). Stepwise activation of the ATR signaling pathway upon increasing RS impacts fragile site integrity. PLoS Genet., 9.","DOI":"10.1371\/journal.pgen.1003643"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"4507","DOI":"10.1007\/s00018-014-1718-9","article-title":"Replication fork recovery and regulation of common fragile sites stability","volume":"71","author":"Franchitto","year":"2014","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Khamidullina, A.I., Abramenko, Y.E., Bruter, A.V., and Tatarskiy, V.V. (2024). Key proteins of replication stress response and cell cycle control as cancer therapy targets. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25021263"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3475","DOI":"10.1038\/sj.onc.1210994","article-title":"Cdc7 kinase mediates Claspin phosphorylation in DNA replication checkpoint","volume":"27","author":"Kim","year":"2008","journal-title":"Oncogene"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.4161\/cc.24675","article-title":"Cdc7-dependent and -independent phosphorylation of Claspin in the induction of the DNA replication checkpoint","volume":"12","author":"Rainey","year":"2013","journal-title":"Cell Cycle"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"e50796","DOI":"10.7554\/eLife.50796","article-title":"Cdc7 activates replication checkpoint by phosphorylating the Chk1 binding domain of Claspin in human cells","volume":"8","author":"Yang","year":"2019","journal-title":"eLife"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"111375","DOI":"10.1016\/j.celrep.2022.111375","article-title":"Regulation of Claspin by the p38 stress-activated protein kinase protects cells from DNA damage","volume":"40","author":"Ulsamer","year":"2022","journal-title":"Cell Rep."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"4946","DOI":"10.1073\/pnas.1400683111","article-title":"STAT3 interrupts ATR-Chk1 signaling to allow oncovirus-mediated cell proliferation","volume":"111","author":"Koganti","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"7022","DOI":"10.1158\/0008-5472.CAN-09-0925","article-title":"Human papillomavirus 16 E7 oncoprotein attenuates DNA damage checkpoint control by increasing the proteolytic turnover of Claspin","volume":"69","author":"Spardy","year":"2009","journal-title":"Cancer Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"30282","DOI":"10.1074\/jbc.M109.093963","article-title":"Polo-like kinase 1 activated by the hepatitis B virus X protein attenuates both the DNA damage checkpoint and DNA repair resulting in partial polyploidy","volume":"285","author":"Studach","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1002\/jcb.21609","article-title":"From G0 to S phase: A view of the roles played by the retinoblastoma (Rb) family members in the Rb-E2F pathway","volume":"102","author":"Sun","year":"2007","journal-title":"J. Cell Biochem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1074\/jbc.M508455200","article-title":"Structure of the human papillomavirus E7 oncoprotein and its mechanism for inactivation of the retinoblastoma tumor suppressor","volume":"281","author":"Liu","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/0092-8674(93)90384-3","article-title":"The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53","volume":"75","author":"Scheffner","year":"1993","journal-title":"Cell"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"8672","DOI":"10.1158\/0008-5472.CAN-05-4443","article-title":"Chk1- and Claspin-dependent but ATR\/ATM- and Rad17-independent DNA replication checkpoint response in HeLa cells","volume":"66","author":"Florensa","year":"2006","journal-title":"Cancer Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"e16431","DOI":"10.15252\/emmm.202216431","article-title":"Actionable loss of SLF2 drives B-cell lymphomagenesis and impairs the DNA damage response","volume":"15","author":"Zhang","year":"2023","journal-title":"EMBO Mol. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.3892\/ijo.2017.3904","article-title":"Deubiquitinating enzyme USP20 is a positive regulator of claspin and suppresses the malignant characteristics of gastric cancer cells","volume":"50","author":"Wang","year":"2017","journal-title":"Int. J. Oncol."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Bold, I.T., Specht, A.-K., Droste, C.F., Zielinski, A., Meyer, F., Clauditz, T.S., Munsher, A., Werner, S., Rothkamm, K., and Petersen, C. (2021). DNA damage response during replication correlates with CIN70 score and determines survival in HNSCC patients. Cancers, 13.","DOI":"10.3390\/cancers13061194"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Hunter, J.E., Butterworth, J.A., Sellier, H., Luli, S., Floudas, A., Moore, A.J., Thomas, H.D., Campbell, K., Kenneth, N., and Chiremba, T. (2018). Regulation of checkpoint kinase signalling and tumorigenesis by the NF-\u03baB regulated gene, CLSPN. BioRxiv.","DOI":"10.1101\/358291"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Azenha, D., Hernandez-Perez, S., Martin, Y., Viegas, M.S., Martins, A., Lopes, M.C., Lam, E.W., Freire, R., and Martins, T.C. (2020). Implications of CLSPN variants in cellular function and susceptibility to cancer. Cancers, 12.","DOI":"10.3390\/cancers12092396"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.canlet.2007.11.003","article-title":"Germline alterations in the CLSPN gene in breast cancer families","volume":"261","author":"Erkko","year":"2008","journal-title":"Cancer Lett."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"S172","DOI":"10.1016\/S0959-8049(12)71365-5","article-title":"Claspin mutations and loss of function may contribute to breast carcinogenesis and gliomagenesis","volume":"48","author":"Madeira","year":"2012","journal-title":"Eur. J. Cancer"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"S43","DOI":"10.1016\/S1359-6349(08)71339-9","article-title":"Loss of expression of Claspin in tumour cells may be involved in breast carcinogenesis","volume":"6","author":"Madeira","year":"2008","journal-title":"Eur. J. Cancer"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1158\/0008-5472.CAN-07-6272","article-title":"Mutational analysis of thirty-two double-strand DNA break repair genes in breast and pancreatic cancers","volume":"68","author":"Wang","year":"2008","journal-title":"Cancer Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.1158\/1541-7786.MCR-09-0033","article-title":"Prevalence and functional analysis of sequence variants in the ATR checkpoint mediator Claspin","volume":"7","author":"Zhang","year":"2009","journal-title":"Mol. Cancer Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.4161\/cc.10.10.15562","article-title":"Characterization of functional domains in human Claspin","volume":"10","author":"Kemp","year":"2011","journal-title":"Cell Cycle"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"e605","DOI":"10.1002\/mgg3.605","article-title":"Exome sequencing in 51 early onset non-familial CRC cases","volume":"7","author":"Thutkawkorapin","year":"2019","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1111\/febs.14594","article-title":"Claspin\u2014Checkpoint adaptor and DNA replication factor","volume":"286","author":"Smits","year":"2019","journal-title":"FEBS J."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Hsieh, M.-J., Lo, Y.-S., Ho, H.-Y., Lin, C.-C., and Chuang, Y.-C. (2024). The interaction between CLSPN gene polymorphisms and alcohol consumption contributes to oral cancer progression. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25021098"},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Johmura, Y., Yamashita, E., Shimada, M., Nakanishi, K., and Nakanishi, M. (2016). Defective DNA repair increases susceptibility to senescence through extension of Chk1-mediated G2 checkpoint activation. Sci. Rep., 6.","DOI":"10.1038\/srep31194"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1093\/nar\/gkac011","article-title":"TRIM21 suppresses CHK1 activation by preferentially targeting CLASPIN for K63-linked ubiquitination","volume":"50","author":"Zhu","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1186\/1479-5876-10-132","article-title":"Claspin as a biomarker of human papillomavirus-related high grade lesions of uterine cervix","volume":"10","author":"Benevolo","year":"2012","journal-title":"J. Transl. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1038\/s41467-019-08886-8","article-title":"Overexpression of Claspin and Timeless protects cancer cells from RS in a checkpoint-independent manner","volume":"10","author":"Bianco","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1111\/cas.14299","article-title":"Claspin overexpression is associated with high-grade histology and poor prognosis in renal cell carcinoma","volume":"111","author":"Kobayashi","year":"2020","journal-title":"Cancer Sci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1007\/s00428-021-03239-7","article-title":"Clinicopathological significance of claspin overexpression and its efficacy as a novel biomarker for the diagnosis of urothelial carcinoma","volume":"480","author":"Kobayashi","year":"2022","journal-title":"Virchows Arch."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.humpath.2018.09.001","article-title":"Clinicopathological significance of claspin overexpression and its association with spheroid formation in gastric cancer","volume":"84","author":"Kobayashi","year":"2019","journal-title":"Hum. Pathol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"103345","DOI":"10.1016\/j.retram.2022.103345","article-title":"CLSPN is a potential biomarker associated with poor prognosis in low-grade gliomas based on a multi-database analysis","volume":"70","author":"Jia","year":"2022","journal-title":"Curr. Res. Translat. Med."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"5574","DOI":"10.1002\/cam4.4113","article-title":"Overexpression of Claspin promotes docetaxel resistance and is associated with prostate-specific antigen recurrence in prostate cancer","volume":"10","author":"Babasaki","year":"2021","journal-title":"Cancer Med."},{"key":"ref_100","first-page":"131","article-title":"Claspin overexpression promotes tumor progression and predicts poor clinical outcome in prostate cancer","volume":"25","author":"Cai","year":"2021","journal-title":"Gene Ther. Mol. Biol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"6422","DOI":"10.21608\/ejhm.2022.270276","article-title":"Immunohistochemical expression of Claspin and TopBP1 in prostatic adenocarcinoma: Correlation with clinicopathological parameters and prognostic significance","volume":"89","author":"Elbasateeny","year":"2022","journal-title":"Egypt. J. Hosp. Med."},{"key":"ref_102","first-page":"1356","article-title":"Bioinformatics analysis of the interactions among lncRNA, miRNA, and mRNA expression, genetic mutations, and epigenetic modifications in hepatocellular carcinoma","volume":"19","author":"Lin","year":"2019","journal-title":"Mol. Med. Rep."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"3267","DOI":"10.7150\/jca.29986","article-title":"Integrated analysis of competing endogenous RNA network revealing potential prognostic biomarkers of hepatocellular carcinoma","volume":"10","author":"Liao","year":"2019","journal-title":"J. Cancer"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1128\/JVI.01515-08","article-title":"Simian virus 40 large T antigen disrupts genome integrity and activates a DNA damage response via Bub1 binding","volume":"83","author":"Hein","year":"2009","journal-title":"J. Virol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"10727","DOI":"10.1128\/JVI.00122-10","article-title":"Simian virus 40 activates ATR-Delta p53 signaling to override cell cycle and DNA replication control","volume":"84","author":"Rohaly","year":"2010","journal-title":"J. Virol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/978-1-62703-236-0_4","article-title":"p53 and cell cycle effects after DNA damage","volume":"962","author":"Senturk","year":"2013","journal-title":"Methods Mol. Biol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1186\/s12935-021-02396-8","article-title":"p53 signaling in cancer progression and therapy","volume":"21","author":"Marei","year":"2021","journal-title":"Cancer Cell Int."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"e30","DOI":"10.1038\/oncsis.2012.29","article-title":"DNA replication stress response involving PLK1, CDC6, POLQ, RAD51 and CLASPIN upregulation prognoses the outcome of early\/mid-stage non-small cell lung cancer patients","volume":"1","author":"Rouquette","year":"2012","journal-title":"Oncogenesis"},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Briu, L.M., Maric, C., and Cadoret, J.C. (2021). Replication stress, genomic instability, and replication timing: A complex relationship. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094764"},{"key":"ref_110","first-page":"1607455","article-title":"Overexpression of the Fork Protection Complex: A strategy to tolerate oncogene-induced RS in cancer cells","volume":"6","author":"Pasero","year":"2019","journal-title":"Cell Cycle"},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Bartek, J., Mistrik, M., and Bartkova, J. (2012). Thresholds of replication stress signaling in cancer development and treatment. Nat. Struct. Mol. Biol., 19.","DOI":"10.1038\/nsmb.2220"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1016\/j.dnarep.2010.09.012","article-title":"The ATR barrier to replication-born DNA damage","volume":"9","year":"2010","journal-title":"DNA Repair"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"9693","DOI":"10.1158\/0008-5472.CAN-10-2286","article-title":"Combining ATR suppression with oncogenic Ras synergistically increases genomic instability, causing synthetic lethality or tumorigenesis in a dosage-dependent manner","volume":"70","author":"Gilad","year":"2010","journal-title":"Cancer Res."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"3164","DOI":"10.1038\/sj.emboj.7600315","article-title":"ATR functions as a gene dosage-dependent tumor suppressor on a mismatch repair-deficient background","volume":"23","author":"Fang","year":"2004","journal-title":"EMBO J."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1084\/jem.20112147","article-title":"An extra allele of Chk1 limits oncogene-induced replicative stress and promotes transformation","volume":"209","author":"Specks","year":"2012","journal-title":"J. Exp. Med."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"2345","DOI":"10.1042\/BCJ20220461","article-title":"Keeping relApse in Chk: Molecular mechanisms of Chk1 inhibitor resistance in lymphoma","volume":"479","author":"Black","year":"2022","journal-title":"Biochem. J."},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Wee, P., and Wang, Z. (2017). Epidermal growth factor receptor cell proliferation signaling pathways. Cancers, 9.","DOI":"10.3390\/cancers9050052"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/10985549.2022.2160598","article-title":"Claspin is Required for Growth Recovery from Serum Starvation through Regulating the PI3K-PDK1-mTOR Pathway in Mammalian Cells","volume":"43","author":"Yang","year":"2023","journal-title":"Mol. Cell. Biol."},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Peng, Y., Wang, Y., Zhou, C., Mei, W., and Zeng, C. (2022). PI3K\/Akt\/mTOR pathway and its role in cancer therapeutics: Are we making headway?. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.819128"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.cell.2011.07.014","article-title":"A ceRNA hypothesis: The Rosetta Stone of a hidden RNA language?","volume":"146","author":"Salmena","year":"2011","journal-title":"Cell"},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Hu, T., Lei, D., Zhou, J., and Zhang, B. (2021). circRNA derived from CLSPN (circCLSPN) is an oncogene in human glioblastoma multiforme by regulating cell growth, migration, and invasion via ceRNA pathway. J. Biosci., 46.","DOI":"10.1007\/s12038-021-00185-z"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1002\/path.2095","article-title":"Evaluation of claspin as a proliferation marker in human cancer and normal tissues","volume":"211","author":"Tsimaratou","year":"2007","journal-title":"J. Pathol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/s42764-021-00049-8","article-title":"Roles of Claspin in regulation of DNA replication, replication stress responses, and oncogenesis in human cells","volume":"2","author":"Hsiao","year":"2021","journal-title":"Genome Instab. Dis."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"2057","DOI":"10.1007\/s00262-023-03388-5","article-title":"Cisplatin resistance driver Claspin is a target for immunotherapy in urothelial carcinoma","volume":"72","author":"Yamada","year":"2023","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/s41389-018-0034-x","article-title":"Double agents: Genes with both oncogenic and tumor-suppressor functions","volume":"7","author":"Shen","year":"2018","journal-title":"Oncogenesis"},{"key":"ref_126","doi-asserted-by":"crossref","unstructured":"Datta, N., Chakraborty, S., Basu, M., and Ghosh, M.K. (2020). Tumor suppressors having oncogenic functions: The double agents. Cells, 10.","DOI":"10.3390\/cells10010046"},{"key":"ref_127","doi-asserted-by":"crossref","unstructured":"Pitolli, C., Wang, Y., Candi, E., Shi, Y., Melino, G., and Amelio, I. (2019). p53-mediated tumor suppression: DNA-damage response and alternative mechanisms. Cancers, 11.","DOI":"10.3390\/cancers11121983"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1038\/cdd.2015.53","article-title":"TP53: An oncogene in disguise","volume":"22","author":"Soussi","year":"2015","journal-title":"Cell Death Diff."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1093\/jmcb\/mjaa040","article-title":"Gain-of-function mutant p53 in cancer progression and therapy","volume":"12","author":"Zhang","year":"2020","journal-title":"J. Mol. Cell Biol."},{"key":"ref_130","doi-asserted-by":"crossref","unstructured":"Choi, W., and Lee, E.S. (2022). Therapeutic targeting of DNA damage response in cancer. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031701"},{"key":"ref_131","doi-asserted-by":"crossref","unstructured":"Rose, M., Burgess, J.T., O\u2019Byrne, K., Richard, D.J., and Bolderson, E. (2020). PARP inhibitors: Clinical relevance, mechanisms of action and tumor resistance. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.564601"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1186\/1476-4598-13-211","article-title":"TopBP1 and Claspin contribute to the radioresistance of lung cancer brain metastases","volume":"13","author":"Choi","year":"2014","journal-title":"Mol. Cancer"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1158\/1078-0432.CCR-19-1515","article-title":"Smoothened promotes glioblastoma radiation resistance via activating USP3-mediated claspin deubiquitination","volume":"26","author":"Tu","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"17512","DOI":"10.18632\/oncotarget.24776","article-title":"The HNF-1\u03b2-USP28-Claspin pathway upregulates DNA damage-induced Chk1 activation in ovarian clear cell carcinoma","volume":"9","author":"Ito","year":"2018","journal-title":"Oncotarget"},{"key":"ref_135","doi-asserted-by":"crossref","unstructured":"Busato, F., Khouzai, B.E., and Mognato, M. (2022). Biological mechanisms to reduce radioresistance and increase the efficacy of radiotherapy: State of the art. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231810211"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"101959","DOI":"10.1016\/j.jddst.2020.101959","article-title":"Docetaxel: An update on its molecular mechanisms, therapeutic trajectory and nanotechnology in the treatment of breast, lung, and prostate cancer","volume":"60","author":"Imran","year":"2020","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_137","doi-asserted-by":"crossref","unstructured":"Corno, C., D\u2019Arcy, P., Bagnoli, M., Paolini, B., Constantino, M., Carenini, N., Corna, E., Alberti, P., Mezzanzanica, D., and Colombo, D. (2022). The deubiquitinase USP8 regulates ovarian cancer cell response to cisplatin by suppressing apoptosis. Front. Cell. Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.1055067"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"7","DOI":"10.13005\/bpj\/1608","article-title":"Review on pharmacology of cisplatin: Clinical use, toxicity, and mechanism of resistance of cisplatin","volume":"12","author":"Aldossary","year":"2019","journal-title":"Biomed. Pharmacol. J."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1158\/1078-0432.CCR-15-2240","article-title":"Molecular pathways: Revisiting glycogen synthase kinase-3\u03b2 as a target for the treatment of cancer","volume":"23","author":"Walz","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1016\/j.canlet.2016.07.006","article-title":"GSK-3 inhibition overcomes chemoresistance in human breast cancer","volume":"380","author":"Ugolkov","year":"2016","journal-title":"Cancer Lett."},{"key":"ref_141","doi-asserted-by":"crossref","unstructured":"Cabrera, E., Raninga, P., Khanna, K.K., and Freire, R. (2019). GSK3-\u03b2 Stimulates Claspin Degradation via \u03b2-TrCP Ubiquitin Ligase and Alters Cancer Cell Survival. Cancers, 11.","DOI":"10.3390\/cancers11081073"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/18\/8828\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:43:28Z","timestamp":1760035408000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/18\/8828"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,10]]},"references-count":141,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["ijms26188828"],"URL":"https:\/\/doi.org\/10.3390\/ijms26188828","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2025,9,10]]}}}