| dc.contributor.advisor | Bastians, Holger Prof. Dr. | |
| dc.contributor.author | Lüddecke, Sina | |
| dc.date.accessioned | 2015-10-26T10:16:42Z | |
| dc.date.available | 2015-10-26T10:16:42Z | |
| dc.date.issued | 2015-10-26 | |
| dc.identifier.uri | http://hdl.handle.net/11858/00-1735-0000-0023-965A-C | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-5328 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 570 | de |
| dc.title | CEP72 represents a putative Oncogene that negatively regulates the mitotic Function of Brca1 and induces Chromosomal Instability | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Bastians, Holger Prof. Dr. | |
| dc.date.examination | 2015-10-15 | |
| dc.description.abstracteng | Proper 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
stability. | de |
| dc.contributor.coReferee | Hoyer-Fender, Sigrid Prof. Dr. | |
| dc.subject.eng | chromosomal instability | de |
| dc.subject.eng | Brca1 | de |
| dc.subject.eng | Cep72 | de |
| dc.subject.eng | mitosis | de |
| dc.subject.eng | aneuploidy | de |
| dc.subject.eng | CIN | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-11858/00-1735-0000-0023-965A-C-2 | |
| dc.affiliation.institute | Biologische Fakultät für Biologie und Psychologie | de |
| dc.subject.gokfull | Biologie (PPN619462639) | de |
| dc.identifier.ppn | 837858860 | |