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CENP-A overexpression promotes distinct fates in human cells, depending on p53

LabEx DEEP
03/31/2021
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New publication from the team of Geneviève Almouzni (UMR3664)

Jeffery D, Gatto A, Podsypanina K, Renaud-Pageot C, Ponce Landete R, Bonneville L, Dumont M, Fachinetti D, Almouzni G
2021, March, Communications Biology
CENP-A overexpression in MCF10-2A cells, commonly used non-tumoural breast epithelial cells. Left panel: condensed dividing chromosomes with bright dots of CENP-A marking the centromeres. Right panel: upon induction of CENP-A overexpression, CENP-A is massively increased at the centromeres and also mis-incorporated all over the chromosome arms.
CENP-A overexpression in MCF10-2A cells, commonly used non-tumoural breast epithelial cells. Left panel: condensed dividing chromosomes with bright dots of CENP-A marking the centromeres. Right panel: upon induction of CENP-A overexpression, CENP-A is massively increased at the centromeres and also mis-incorporated all over the chromosome arms.

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, single-cell RNA-sequencing and cell trajectory analysis, 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. Surprisingly, when we inactivate p53, CENP-A overexpression instead promotes epithelial-mesenchymal transition, an essential process in mammalian development but also a precursor for tumour cell invasion and metastasis. Thus, we uncover an unanticipated function of CENP-A overexpression to promote cell fate reprogramming, with important implications for development and tumour evolution.

Jeffery D, Gatto A, Podsypanina K, Renaud-Pageot C, Ponce Landete R, Bonneville L, Dumont M, Fachinetti D, Almouzni G
2021, March, Communications Biology