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

Abstract : Abstract 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.
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https://hal-cnrs.archives-ouvertes.fr/hal-03452720
Contributor : Daniele Fachinetti Connect in order to contact the contributor
Submitted on : Saturday, November 27, 2021 - 12:35:42 PM
Last modification on : Sunday, November 28, 2021 - 3:34:34 AM

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Daniel Jeffery, Alberto Gatto, Katrina Podsypanina, Charlène Renaud-Pageot, Rebeca Ponce Landete, et al.. CENP-A overexpression promotes distinct fates in human cells, depending on p53 status. Communications Biology, Nature Publishing Group, 2021, 4 (1), ⟨10.1038/s42003-021-01941-5⟩. ⟨hal-03452720⟩

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