Whole genome duplication through mitotic slippage causes nuclear instability

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.