ADARp150 counteracts whole genome duplication

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 ADAR...

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Veröffentlicht in:	Nucleic acids research Jg. 52; H. 17; S. 10370 - 10384
Hauptverfasser:	van Gemert, Frank, Drakaki, Alexandra, Lozano, Isabel Morales, de Groot, Daniël, Uiterkamp, Maud Schoot, Proost, Natalie, Lieftink, Cor, van de Ven, Marieke, Beijersbergen, Roderick L, Jacobs, Heinz, te Riele, Hein
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	England Oxford University Press 23.09.2024
Schlagworte:	Genome Integrity, Repair and
ISSN:	0305-1048, 1362-4962, 1362-4962
Online-Zugang:	Volltext
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Zusammenfassung:	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. Graphical Abstract Graphical Abstract
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0305-1048 1362-4962 1362-4962
DOI:	10.1093/nar/gkae700