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Essential role for centromeric factors following p53 loss and oncogenic transformation. | LitMetric

AI Article Synopsis

  • In mammals, the centromere is defined by the histone variant CENP-A, which is regulated by its chaperone HJURP; disruptions in this process can lead to issues with chromosome segregation and result in genomic instability, particularly in cancer.
  • In p53-null human tumors and mouse models, both CENP-A and HJURP are found to be increased, indicating a potential link between p53 inactivation and the up-regulation of these proteins.
  • Depleting HJURP using CRISPR/Cas9 has different effects based on p53 status: while it triggers cell cycle arrest in cells with functioning p53, it causes severe chromosome imbalances and cell death in p

Article Abstract

In mammals, centromere definition involves the histone variant CENP-A (centromere protein A), deposited by its chaperone, HJURP (Holliday junction recognition protein). Alterations in this process impair chromosome segregation and genome stability, which are also compromised by p53 inactivation in cancer. Here we found that CENP-A and HJURP are transcriptionally up-regulated in p53-null human tumors. Using an established mouse embryonic fibroblast (MEF) model combining p53 inactivation with E1A or HRas-V12 oncogene expression, we reproduced a similar up-regulation of HJURP and CENP-A. We delineate functional CDE/CHR motifs within the and promoters and demonstrate their roles in p53-mediated repression. To assess the importance of HJURP up-regulation in transformed murine and human cells, we used a CRISPR/Cas9 approach. Remarkably, depletion of HJURP leads to distinct outcomes depending on their p53 status. Functional p53 elicits a cell cycle arrest response, whereas, in p53-null transformed cells, the absence of arrest enables the loss of HJURP to induce severe aneuploidy and, ultimately, apoptotic cell death. We thus tested the impact of HJURP depletion in pre-established allograft tumors in mice and revealed a major block of tumor progression in vivo. We discuss a model in which an "epigenetic addiction" to the HJURP chaperone represents an Achilles' heel in p53-deficient transformed cells.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5393061PMC
http://dx.doi.org/10.1101/gad.290924.116DOI Listing

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