CENP-A overexpression drives distinct cell fates depending on p53 status

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 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.

Histone Variants: Guardians of Genome Integrity

“…CENPA overexpression also renders cells more tolerant to DNA damage [24], which may strongly compromise genome integrity even if the underlying mechanism is currently not clear. A possible role of p53 in conjunction with CENPA in oncogenesis is suggested by recent studies showing that the p53 status is a key determinant of the impact of HJURP and CENPA overexpression on cell identity, genome stability, and response to therapy [202,203]. At the molecular level, CENPA forms homotypic nucleosomes at centromeres [204], while heterotypic nucleosomes containing both CENPA and H3.3 are observed in CENPA-overexpressing cells [24].…”