Whole-genome duplications (WGDs) have played a central role in the evolution of genomes and constitute an important source of genome instability in cancer. Here, we show in Saccharomyces cerevisiae that abnormal accumulations of histones are sufficient to induce WGDs. Our results link these WGDs to a reduced incorporation of the histone variant H2A.Z to chromatin. Moreover, we show that high levels of histones promote Swe1WEE1 stabilisation thereby triggering the phosphorylation and inhibition of Cdc28CDK1 through a mechanism different of the canonical DNA damage response. Our results link high levels of histones to a specific type of genome instability that is quite frequently observed in cancer and uncovers a new mechanism that might be able to respond to high levels of histones.

We thank A Gunjan, J Tyler, S Biggins, F Prado, Doug Kellogg, and S Mahajan for sharing strains, plasmids and/or reagents; We would also like to thank C Machu for imaging expertise and JH Guervilly, Felix Prado, E Bailly and V Geli team members for discussions. DM was supported by a postdoctoral fellowship from the Association pour la Recherche sur le Cancer (Fondation ARC). Work in VG laboratory is supported by the”Ligue contre le Cancer’ (Equipe Labéllisée 2017). Work in the laboratory of M M is supported of the European Research Council (ERC) Starting Grant 2010-St-20091118, and the Spanish Ministry of Economy and Competitiveness BFU2012-37162 to MM, and ‘Centro de Excelencia Severo Ochoa 2013–2017’, SEV-2012–0208 to the CRG. S C is supported by grants BFU2013-48643-C3-1-P from the Spanish MiNECO, and P12-BIO1938MO from the Regional Andalusian Government, both incluidng European Union funds (FEDER).