| dc.contributor.advisor | Bastians, Holger Prof. Dr. | |
| dc.contributor.author | Haas, Alexander | |
| dc.date.accessioned | 2024-07-05T14:45:31Z | |
| dc.date.issued | 2024-07-05 | |
| dc.identifier.uri | http://resolver.sub.uni-goettingen.de/purl?ediss-11858/15348 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-10554 | |
| dc.format.extent | 153 | de |
| dc.language.iso | eng | de |
| dc.subject.ddc | 570 | de |
| dc.title | The role of Wnt signalling in the microtubule-mediated maintenance of chromosomal stability | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Bastians, Holger Prof. Dr. | |
| dc.date.examination | 2024-05-06 | de |
| dc.description.abstracteng | Chromosomal instability (CIN) is a major hallmark of cancer and represents a driving force
for tumourigenesis, tumour progression, and the development of therapy resistance. CIN
can be subdivided into structural CIN (S-CIN) and whole chromosomal CIN (W-CIN), which
lead to structural and numerical chromosomal aberrations, respectively. While S-CIN is
caused by DNA replication stress and DNA repair defects, W-CIN is triggered by mitotic
errors. Previously our group showed that abnormally increased mitotic microtubule growth
rates are responsible for perpetual chromosome missegregation, thereby causing aneuploid
karyotypes in human cancer cells. Furthermore, these increases in microtubule polymerisa
tion are triggered by replication stress that is detected in chromosomally unstable human
cancer cells, which might explain the concomitant occurrence of S- and W-CIN. Interest
ingly, the search for players in microtubule-regulated W-CIN has yielded basal Wnt10b/LRP
signalling as a key suppressor of abnormally increased microtubule growth rates and the
subsequent evolvement of aneuploidy. However, the mechanism by which Wnt signalling
influences mitotic chromosome segregation is still unknown.
This study shows that Wnt10b is the main Wnt ligand required for maintaining microtu
bule-mediated chromosomal stability. Wnt10b acts specifically during early S phase, where
loss of Wnt10bsignalling causes immediate increases in microtubule polymerisation without
affecting replication dynamics per se. Also, activation of Wnt10b signalling rescues abnor
mal microtubule polymerisation rates and chromosome missegregation upon replication
stress after its experimental induction or in chromosomally unstable cancer cells that suffer
from endogenous replication stress. Interestingly, this study showed that increased micro
tubule assembly rates are triggered during early S phase and remain elevated until mitosis,
where they promote chromosome missegregation and aneuploidy. Importantly, increased
microtubule polymerisation rates regulated by Wnt10b signalling during early S phase cause
replication stress-associated chromosomal breaks and gaps thereby contributing to S-CIN.
Thus, this study uncovered a novel early S phase-specific link between Wnt10b signalling
and replication stress in regulating the microtubule cytoskeleton, which in turn regulates the
occurrence of S- and W-CIN. | de |
| dc.contributor.coReferee | Hahn, Heidi Prof. Dr. | |
| dc.subject.eng | Wnt10b | de |
| dc.subject.eng | Wnt signalling | de |
| dc.subject.eng | chromosomal instability | de |
| dc.subject.eng | colorectal cancer | de |
| dc.subject.eng | microtubule polymerisation rate | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-ediss-15348-5 | |
| dc.date.embargoed | 2025-05-04 | |
| dc.affiliation.institute | Biologische Fakultät für Biologie und Psychologie | de |
| dc.subject.gokfull | Biologie (PPN619462639) | de |
| dc.description.embargoed | 2025-05-04 | de |
| dc.identifier.ppn | 189440663X | |
| dc.notes.confirmationsent | Confirmation sent 2024-07-05T15:15:01 | de |