Genetic instability from a single S phase after whole-genome duplication
In: ISSN: 0028-0836, 2022
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International audience ; Abstract Diploid and stable karyotypes are associated with health and fitness in animals. By contrast, whole-genome duplications—doublings of the entire complement of chromosomes—are linked to genetic instability and frequently found in human cancers 1–3 . It has been established that whole-genome duplications fuel chromosome instability through abnormal mitosis 4–8 ; however, the immediate consequences of tetraploidy in the first interphase are not known. This is a key question because single whole-genome duplication events such as cytokinesis failure can promote tumorigenesis 9 and DNA double-strand breaks 10 . Here we find that human cells undergo high rates of DNA damage during DNA replication in the first S phase following induction of tetraploidy. Using DNA combing and single-cell sequencing, we show that DNA replication dynamics is perturbed, generating under- and over-replicated regions. Mechanistically, we find that these defects result from a shortage of proteins during the G1/S transition, which impairs the fidelity of DNA replication. This work shows that within a single interphase, unscheduled tetraploid cells can acquire highly abnormal karyotypes. These findings provide an explanation for the genetic instability landscape that favours tumorigenesis after tetraploidization.
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Genetic instability from a single S phase after whole-genome duplication
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Autor/in / Beteiligte Person: | Gemble, Simon ; Wardenaar, René ; Keuper, Kristina ; Srivastava, Nishit ; Nano, Maddalena ; Macé, Anne-Sophie ; Tijhuis, Andréa ; Bernhard, Sara Vanessa ; Spierings, Diana ; Simon, Anthony ; Goundiam, Oumou ; Hochegger, Helfrid ; Piel, Matthieu ; Foijer, Floris ; Storchová, Zuzana ; Basto, Renata ; Institut Curie Paris ; ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010) |
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Zeitschrift: | ISSN: 0028-0836, 2022 |
Veröffentlichung: | HAL CCSD ; Nature Publishing Group, 2022 |
Medientyp: | academicJournal |
DOI: | 10.1038/s41586-022-04578-4 |
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