Centrosome integrity as a determinant of replication stress

by Zainab Tayeh
Doctoral thesis
Date of Examination:2020-01-16
Date of issue:2020-01-29
Advisor:Prof. Dr. Matthias Dobbelstein
Referee:Prof. Dr Bernd Wollnik
Referee:Dr. Roland Dosch
Referee:Prof. Dr. Heidi Hahn
Referee:Dr. Ufuk Günesdogan
Persistent Address: http://dx.doi.org/10.53846/goediss-7816

 

 

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Abstract

English

The centrosome functions as a microtubule-nucleating organelle for the mitotic spindle. Like the whole genome, centrosomes require accurate replication once per cell cycle. Here we show that the impairment of centrosome composition by depletion of centrosomal components or by the inhibition of centrosomal protein PLK4 reduces the progression of DNA replication forks in cancer cells. Importantly, the reduction in fork progression occurs even when the cells cycle are arrested at the G1 phase before damaging the centrosomes, excluding mitotic failure as the source of replication stress. Mechanistically, the kinase MLK3 associates with centrosomes. When the centrosome composition is impaired, MLK3 activates the kinases p38 as well as MK2/MAPKAPK2. RNA:DNA hybrids (R-loops) leading to DNA replication stress occur upon activation of the transcription factor JUN, which is a downstream target of p38. Finally, fibroblasts from Seckel syndrome patients harboring defective centrosomes showed replication stress, which was alleviated by inhibition of MK2. Similar replication stress has been observed upon deletion of the kinase ATR, and this genetic defect also causes Seckel syndrome.
Keywords: polo-like kinase 4 (PLK4), Mitogen-Activated Protein Kinase 11 (MLK3), MAP kinase-activated protein kinase 2 (MK2), Ataxia Telangiectasia And Rad3-Related Protein (ATR)
 
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