Attenuation of the p53 response to DNA damage by high cell density

Regulation of the DNA damage response by p53 cofactors.

The selective expression of p53-targeted genes is central to the p53-mediated DNA damage response. It is affected by multiple factors including posttranslational modifications and cofactors of p53. Here, we proposed an integrated model of the p53 network to characterize how the cellular response is regulated by key cofactors of p53, Hzf and ASPP. We found that the sequential induction of Hzf an...

Constant rate of p53 tetramerization in response to DNA damage controls the p53 response

The dynamics of the tumor suppressor protein p53 have been previously investigated in single cells using fluorescently tagged p53. Such approach reports on the total abundance of p53 but does not provide a measure for functional p53. We used fluorescent protein-fragment complementation assay (PCA) to quantify in single cells the dynamics of p53 tetramers, the functional units of p53. We found t...

Fine-tuning the p53 response to DNA damage

Most cancer treatments exploit the hypersensitivity of rapidly dividing tumor cells to DNA damage, largely reflecting problems with replicating damaged DNA templates. Many cancer chemotherapeutics directly damage DNA, and most types of DNA damage block replication forks. Other classes of chemotherapeutics include antimetabolites that reduce nucleotide pools and starve DNA polymerases or directl...

Downregulation of VRK1 by p53 in Response to DNA Damage Is Mediated by the Autophagic Pathway

Human VRK1 induces a stabilization and accumulation of p53 by specific phosphorylation in Thr18. This p53 accumulation is reversed by its downregulation mediated by Hdm2, requiring a dephosphorylated p53 and therefore also needs the removal of VRK1 as stabilizer. This process requires export of VRK1 to the cytosol and is inhibited by leptomycin B. We have identified that downregulation of VRK1 ...

p53 Response to DNA Damage during S-Phase