TY - JOUR T1 - CENP-A overexpression drives distinct cell fates depending on p53 status JF - bioRxiv DO - 10.1101/2020.07.21.213496 SP - 2020.07.21.213496 AU - Daniel Jeffery AU - Katrina Podsypanina AU - Alberto Gatto AU - Rebeca Ponce Landete AU - Lorraine Bonneville AU - Marie Dumont AU - Daniele Fachinetti AU - Geneviève Almouzni Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/07/21/2020.07.21.213496.abstract N2 - Tumour evolution is driven by both genetic and epigenetic changes. CENP-A, the centromeric histone H3 variant, is an epigenetic mark that directly perturbs genetic stability and chromatin when overexpressed. Although CENP-A overexpression is a common feature of many cancers, how this impacts cell fate and response to therapy remains unclear. Here, we established a tunable system of inducible and reversible CENP-A overexpression combined with a switch in p53 status in human cell lines. Through clonogenic survival assays and single-cell RNA-sequencing over time, we uncover the tumour suppressor p53 as a key determinant of how CENP-A impacts cell state, cell identity and therapeutic response. If p53 is functional, CENP-A overexpression promotes senescence and radiosensitivity. But, when we inactivate p53, CENP-A overexpression instead promotes epithelial-mesenchymal transition, an essential precursor for tumour cell invasion and metastasis. Thus, CENP-A overexpression drives distinct cell fates depending on p53 status, with important implications for tumour evolution.Competing Interest StatementThe authors have declared no competing interest. ER -