1. ADARp150 counteracts whole genome duplication.
- Author
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van Gemert, Frank, Drakaki, Alexandra, Lozano, Isabel, de Groot, Daniël, Uiterkamp, Maud, Proost, Natalie, Lieftink, Cor, van de Ven, Marieke, Beijersbergen, Roderick, Jacobs, Heinz, and Te Riele, Hein
- Subjects
Humans ,Adenosine Deaminase ,RNA-Binding Proteins ,Cell Proliferation ,Mitosis ,Animals ,DNA Replication ,Tetraploidy ,Genome ,Human ,G1 Phase Cell Cycle Checkpoints ,Mice ,RNA Editing ,Cell Line ,Tumor - Abstract
Impaired control of the G1/S checkpoint allows initiation of DNA replication under non-permissive conditions. Unscheduled S-phase entry is associated with DNA replication stress, demanding for other checkpoints or cellular pathways to maintain proliferation. Here, we uncovered a requirement for ADARp150 to sustain proliferation of G1/S-checkpoint-defective cells under growth-restricting conditions. Besides its well-established mRNA editing function in inversely oriented short interspersed nuclear elements (SINEs), we found ADARp150 to exert a critical function in mitosis. ADARp150 depletion resulted in tetraploidization, impeding cell proliferation in mitogen-deprived conditions. Mechanistically we show that ADAR1 depletion induced aberrant expression of Cyclin B3, which was causative for mitotic failure and whole-genome duplication. Finally, we find that also in vivo ADAR1-depletion-provoked tetraploidization hampers tumor outgrowth.
- Published
- 2024