Centrosome impairment causes DNA replication stress through MLK3/MK2 signaling and R-loop formation

Centrosomes support accurate mitosis in many animal cells. However, it remains to be explored whether centrosomes also facilitate the progression through different phases of the cell cycle. Here we show that impairing the composition of centrosomes, by depletion of centrosomal components or by inhib...

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Bibliographic Details
Published inbioRxiv
Main Authors Tayeh, Zainab, Stegmann, Kim, Kleeberg, Antonia, Friedrich, Mascha, Josephine Ann Mun Yee Choo, Wollnik, Bernd, Dobbelstein, Matthias
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 10.01.2020
Subjects
Cell cycle
Centrosomes
Deoxyribonucleic acid
DNA
DNA biosynthesis
Dwarfism
Fibroblasts
Hybrids
MAP kinase kinase
Microcephaly
Mitosis
Polo-like kinase
R-loops
Replication forks
Ribonucleic acid
RNA
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Summary:Centrosomes support accurate mitosis in many animal cells. However, it remains to be explored whether centrosomes also facilitate the progression through different phases of the cell cycle. Here we show that impairing the composition of centrosomes, by depletion of centrosomal components or by inhibition of polo-like kinase 4 (PLK4), reduces the progression of DNA replication forks. This occurs even when the cell cycle is arrested before damaging the centrosomes, thus excluding mitotic failure as the source ofreplication stress. Mechanistically, the kinase MLK3 associates with centrosomes. When centrosomes are disintegrated, MLK3 activates the kinases p38 and MK2/MAPKAPK2. Transcription-dependent RNA:DNA hybrids (R-loops) are then causing DNA replication stress. Fibroblasts from patients with microcephalic primordial dwarfism (Seckel syndrome) harbouring defective centrosomes showed replication stress and diminished proliferation, which were each alleviated by inhibition of MK2. Thus, centrosomes not only facilitate mitosis, but their integrity is also supportive in DNA replication.
DOI:10.1101/2020.01.09.898684