Molecular mechanisms of replication stress-induced mitotic chromosome missegregation

by Nicolas Böhly
Doctoral thesis
Date of Examination:2022-11-08
Date of issue:2022-12-09
Advisor:Prof. Dr. Holger Bastians
Referee:Prof. Dr. Holger Bastians
Referee:Prof. Dr. Bernd Wollnik
Persistent Address: http://dx.doi.org/10.53846/goediss-9549

 

 

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Abstract

English

Chromosomal instability (CIN), the process of the generation of structural and numerical changes in the karyotype, is a major hallmark of human cancer generating genetic variation, thereby driving tumor evolution and cellular adaption in human cancer. CIN has therefore been strongly associated with tumorigenesis, therapy resistance and poor clinical outcome.

CIN can be subdivided into structural (S-CIN) and whole chromosomal instability (W- CIN). W-CIN has been directly correlated with errors during mitosis. S-CIN leading to structural chromosome aberrations, on the other hand, has been associated with DNA replication stress (RS) during S-phase.

Recent findings indicate that RS can also cause chromosome segregation defects, thereby linking W-CIN and S-CIN in human cancer. However, the underlying mechanisms of the crosstalk between RS during S-phase and whole chromosome missegregation during mitosis has not been elucidated so far.

In this context, the results of this study show that cancer-relevant mild RS, induces abnormally enhanced mitotic microtubule polymerization rates, a well-described mechanism causing chromosome missegregation in mitosis resulting in aneuploidy in colorectal cancer cells.

Importantly, this study reveals that RS-dependent enhanced origin firing during S-phase but not replication stress per se is a key trigger to cause aneuploidy by enhanced microtubule dynamics and by inducing a DNA damage response. In fact, chromosomally unstable cancer cells show endogenous decreased replication fork progression rates, increased origin firing and upregulated DNA damage responses that contribute to abnormally increased mitotic microtubule polymerization rates and whole chromosome missegregation.

Accordingly, abnormal microtubule polymerization rates and chromosome missegregation can be rescued in chromosomally unstable cancer cells by nucleoside supplementation to counteract endogenous RS by suppressing excessive origin firing and by inhibiting DNA damage signaling.
Thus, this study reveals possible molecular mechanisms of how mild RS causes W- CIN in human cancer."
Keywords: DNA replication stress; chromosomal instability; mitosis; origin firing; cancer; aneuploidy