Whole genome duplication through mitotic slippage causes nuclear instability

Abstract

Whole-genome duplication (WGD), leading to polyploidy can arise in physiological and pathological contexts. WGD can occur via non-canonical cell cycles such as mitotic slippage, cytokinesis failure or endoreplication. Whether the routes to WGD influence the behaviour of the resulting polyploid cells remains unclear. Here, we compared these routes under both physiological and non-physiological conditions. Remarkably, only mitotic slippage led to widespread nuclear abnormalities defined by highly variable nuclear deformations that we termed nuclear instability. Mechanistically, we found that these nuclei were softer and thus more vulnerable to microtubule-driven deformations. The resulting nuclear instability leads to local nuclear reorganisation and changes in 3D genome organisation. Importantly, we observed similar nuclear instability in megakaryocytes, which are physiological polyploid cells generated by mitotic slippage, providing a molecular mechanism for their atypical nuclear architecture. In striking contrast, nuclear shape was stable in different physiological polyploid cells generated by cytokinesis failure and endoreplication. Overall, our findings highlight that the route towards WGD matters and that mitotic slippage uniquely destabilizes nuclear architecture, with implications for both physiology and disease.

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Cite

BibTeX RIS

BibTeX

@article{gemble2026whole,
  title = {{Whole genome duplication through mitotic slippage causes nuclear instability}},
  author = {Simon Gemble and Margot Budzyk and Anthony Simon and Ruxandra Lambuta and Luca Nanni and Nicole Weiss and Audrey Forest and Yekaterina Miroshnikova and Federica Scotto Di Carlo and Véronique Marthiens and Corentin Verdel and Jing Fang and Chantal Desdouets and Sara Wickström and Giovanni Ciriello and Elisa Oricchio and Geneviève Almouzni and Renata Basto},
  journal = {The EMBO Journal},
  year = {2026},
  month = sep,
  doi = {10.1038/s44318-026-00912-y},
  url = {https://hal.science/hal-05762753v1},
  note = {CC BY 4.0},
}

RIS

TY  - JOUR
TI  - Whole genome duplication through mitotic slippage causes nuclear instability
AU  - Simon Gemble
AU  - Margot Budzyk
AU  - Anthony Simon
AU  - Ruxandra Lambuta
AU  - Luca Nanni
AU  - Nicole Weiss
AU  - Audrey Forest
AU  - Yekaterina Miroshnikova
AU  - Federica Scotto Di Carlo
AU  - Véronique Marthiens
AU  - Corentin Verdel
AU  - Jing Fang
AU  - Chantal Desdouets
AU  - Sara Wickström
AU  - Giovanni Ciriello
AU  - Elisa Oricchio
AU  - Geneviève Almouzni
AU  - Renata Basto
PY  - 2026
DA  - 2026/09/19
JO  - The EMBO Journal
DO  - 10.1038/s44318-026-00912-y
UR  - https://hal.science/hal-05762753v1
AB  - Whole-genome duplication (WGD), leading to polyploidy can arise in physiological and pathological contexts. WGD can occur via non-canonical cell cycles such as mitotic slippage, cytokinesis failure or endoreplication. Whether the routes to WGD influence the behaviour of the resulting polyploid cells remains unclear. Here, we compared these routes under both physiological and non-physiological conditions. Remarkably, only mitotic slippage led to widespread nuclear abnormalities defined by highly variable nuclear deformations that we termed nuclear instability. Mechanistically, we found that these nuclei were softer and thus more vulnerable to microtubule-driven deformations. The resulting nuclear instability leads to local nuclear reorganisation and changes in 3D genome organisation. Importantly, we observed similar nuclear instability in megakaryocytes, which are physiological polyploid cells generated by mitotic slippage, providing a molecular mechanism for their atypical nuclear architecture. In striking contrast, nuclear shape was stable in different physiological polyploid cells generated by cytokinesis failure and endoreplication. Overall, our findings highlight that the route towards WGD matters and that mitotic slippage uniquely destabilizes nuclear architecture, with implications for both physiology and disease.
SN  - 0261-4189
SN  - 1460-2075
ER  -

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