Taken together, these oncotarget results indicate that the CTD and OD domains of mtp53 R273H play critical roles in mutant p53 GOF related to processes associated with DNA replication

Oncotarget released “Frameshift-mediated reduction of gain-of-function p53 R273H and deletion of the R273H C-terminus in breast cancer cells lead to replication-stress-sensitivity“Who reported that these authors recently documented that the gain-of-function mutant p53 R273H interacts with replicating DNA and PARP1 in triple negative breast cancer cells. The Missense R273H GOF mtp53 has a mutated central DNA binding domain that makes it impossible for it to bind specifically to DNA, but retains the ability to interact closely with chromatin.

Both the C-terminal domain and the oligomerization domain of GOF mtp53 proteins are intact and it is unclear whether these regions of mtp53 are responsible for chromatin-based DNA replication activities.

These included a frame-shifted mtp53 R273Hfs387 that decreased mtp53 protein expression; mtp53 R273HΔ381-388, which had a small deletion within the CTD; and mtp53 R273HΔ347-393 in which both the OD and CTD regions were truncated.

The mtp53 R273HΔ347-393 existed exclusively as monomers and disrupted the chromatin interaction of mtp53 R273H.

Taken together these Oncotarget The results show that the CTD and OD domains of mtp53 R273H play critical roles in mutant p53 GOF related to processes associated with DNA replication.

Taken together these Oncotarget The results show that the CTD and OD domains of mtp53 R273H play critical roles in mutant p53 GOF related to processes associated with DNA replication.

Dr. Jill Bargonetti said: “The tumor suppressor protein p53 is well known as a transcription factor, but p53 also has non-transcriptional functions.

While tumor-derived missense mtp53 proteins have altered functions, they contain the two N-terminal transactivation domains, followed by a proline-rich domain, an altered central DNA-binding domain and the oligomerization domain and the C-terminal regulatory domain.

Here they are further investigating the ability of mtp53 R273H and its OD and CTD regions to influence cell proliferation, DNA replication and the cell cycle progression of breast cancer cells.

The decision to investigate a possible role for the OD and CTD domains in the context of the mtp53 R273H allele was twofold:

  1. With this in mind, they outlined the GOF pathway above and, in parallel with the studies reported, worked to develop more tools to elucidate the role of each domain in mtp53 GOF activity;
  2. Their pursuit of a genetic approach using CRISPR-Cas9 technology to create specific changes within each domain required that we first focus on an mtp53 R273H expressing cell line.

They saw that a frameshift mutation at the C-terminal end of mtp53 reduced stable mtp53-R273H protein levels compared to parental MDA-MB-468 cells, reduced cell proliferation, and reduced the chromatin association of replication proteins that theirs slow progression through S-phase.

CRISPR-Cas9 targeting also produced cell clones with C-terminally truncated mtp53-R273H proteins; those cells with truncated mtp53 R273H showed reduced proliferation compared to the parent cells, but similarly progressed through the S-phase.

The Bargonetti Research Team concluded in his Oncotarget Research shows that their current studies do not indicate a specific function performed by the OD and CTD domains in response to thymidine; However, they can show that their loss does not affect replisome composition at the onset of S phase as measured by PCNA chromatin loading, and they will address this result in the future.

Thus, the function (s) of the OD and CTD domains correlate with events after entering S-phase, in contrast to this function conferred by other p53 domain (s) deficient in the mtp53fs387 cell line, the loss of which prevents entry into the S phase. Although the authors are currently unable to articulate the exact roles of these different regions of p53 in response to thymidine, their studies suggest that they could function at different time stages of the S phase.

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DOI – https: //doi.Organization/10.18632 /onkoziel.27975

Full text – https: //www.onkoziel.com /Items/27975 /Text/

Correspondence – Jill Bargonetti – [email protected]

keywords
mutant p53,
Functional gain,
Oligomerization,
DNA replication,
Frame shift

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