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CEP72 represents a putative Oncogene that negatively regulates the mitotic Function of Brca1 and induces Chromosomal Instability

dc.contributor.advisorBastians, Holger Prof. Dr.
dc.contributor.authorLüddecke, Sina
dc.titleCEP72 represents a putative Oncogene that negatively regulates the mitotic Function of Brca1 and induces Chromosomal Instabilityde
dc.contributor.refereeBastians, Holger Prof. Dr.
dc.description.abstractengProper progression through mitosis ensures the maintenance of whole chromosomal stability in a eukaryotic cell. Hence, failures during this tightly regulated process can lead to the perpetual mis-segregation of whole chromosomes, which is referred to as chromosomal instability (CIN). This process results in the generation of aneuploidy and an increased genetic variability contributing to tumourigenesis and tumour progression. Although CIN is a major hallmark of human cancer, the underlying mechanisms leading to perpetual chromosome mis-segregation during mitosis are largely unknown. Interestingly, the tumour suppressor Brca1 and its positive regulator Chk2 were found to be crucial for the proper regulation of spindle microtubule plus end polymerization within mitotic spindles, which is pivotal for correct microtubule-kinetochore attachments and faithful chromosome segregation. Consequently, loss of the CHK2-BRCA1 axis leads to enhanced spindle microtubule plus end assembly and the induction of CIN. Despite the importance of these findings the underlying molecular mechanism remained elusive and the regulation of Brca1 during mitosis is still poorly understood. In this study we identified the centrosomal protein Cep72 as a novel Brca1-interacting protein. Importantly, Cep72 was found to be frequently upregulated in human colorectal cancer suggesting that CEP72 represents a putative oncogene. Overexpression of CEP72 mirrors mitotic defects seen upon loss of BRCA1 or its positive regulator CHK2, indicating a possible function for Cep72 in negatively regulating Brca1 during mitosis. In detail, overexpression of CEP72 results in enhanced spindle microtubule plus end polymerization rates causing spindle assembly defects, lagging chromosomes and the induction of CIN. Intriguingly, these defects can be suppressed by concomitantly increasing the levels of the positive Brca1 regulator Chk2. Vice versa, reducing the Cep72 protein levels restores proper microtubule plus end polymerization and spindle assembly in cells with a partial loss of CHK2. Thus, my results suggest that the mitotic function of Brca1 is positively regulated by Chk2, and counteracted by Cep72. Furthermore, the balanced regulation of Brca1 by Chk2 and Cep72 seems to be crucial for proper microtubule dynamics and accurate chromosome segregation ensuring the maintenance of whole chromosomal
dc.contributor.coRefereeHoyer-Fender, Sigrid Prof. Dr.
dc.subject.engchromosomal instabilityde
dc.affiliation.instituteBiologische Fakultät für Biologie und Psychologiede
dc.subject.gokfullBiologie (PPN619462639)de

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