New findings on the link between CRISPR gene-editing and mutated cancer
cells

Date:
November 18, 2021
Source:
Karolinska Institutet
Summary:
A protein that protects cells from DNA damage, p53, is activated
during gene editing using the CRISPR technique. Consequently,
cells with mutated p53 have a survival advantage, which can cause
cancer. Researchers have found new links between CRISPR, p53 and
other cancer genes that could prevent the accumulation of mutated
cells without compromising the gene scissors' effectiveness.



FULL STORY ==========================================================================
A protein that protects cells from DNA damage, p53, is activated during
gene editing using the CRISPR technique. Consequently, cells with mutated
p53 have a survival advantage, which can cause cancer. Researchers at Karolinska Institutet in Sweden have found new links between CRISPR,
p53 and other cancer genes that could prevent the accumulation of mutated
cells without compromising the gene scissors' effectiveness. The study, published in Cancer Research, can contribute to tomorrow's precision
medicine.


==========================================================================
Much hope is being pinned on the potential of gene editing using the
CRISPR (gene scissors) method as a crucial part in the precision medicine
of the future. However, before the method can become hospital routine,
several hurdles need to be overcome.

One of these challenges is associated with how cells behave when
subjected to DNA damage, which CRISPR gene editing causes in a controlled fashion. Damage to cells activates the protein p53, which acts as the
cell's "first aid" response to DNA damage.

It is already known that the technique is less effective when p53 is
active; at the same time, however, a lack of p53 can allow cells to
start growing uncontrollably and become cancerous. In over half of all
cancers the gene for p53 is mutated and thus unable to protect against uncontrolled cell division.

It is therefore important to avoid the enrichment (accumulation) of such mutated cells.

Researchers at Karolinska Institutet have now shown that cells with inactivating mutations of the p53 gene gain a survival advantage when
subjected to CRISPR and can thus accumulate in a mixed cell population.

The researchers have also identified a network of linked genes with
mutations that have a similar effect to p53 mutations, and shown that
the transient inhibition of p53 is a possible pharmaceutical strategy
for preventing the enrichment of cells with such mutations.



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"It can seem contradictory to inhibit p53 in a CRISPR context," says the study's first author Long Jiang, doctoral student at the Department of Medicine, Karolinska Institutet (Solna). "However, some of the literature supports the idea that p53 inhibition can make CRISPR more effective. In
our study we show that this can also counteract the enrichment of cells
with mutations in p53 and a group of associated genes." The research has
a contributory potential to the future clinical implementation of CRISPR
in having identified a network of possible candidate genes that should be carefully controlled for mutations when cells are subjected to the CRISPR technique. Another possible conclusion is that the transient inhibition of
p53 could prove a strategy for reducing the enrichment of mutated cells.

The researchers have also studied the DNA-damage response as a possible
marker in the development of more precise guide RNA sequences, which
are used to show CRISPR where a DNA sequence is to be altered.

"We believe that the up-regulation of genes involved in the DNA damage
response can be a sensitive marker for how much unspecific ('off-target') activity a guide RNA has, and can thus help in the selection of 'safer'
guide RNAs," says the study's last author Fredrik Wermeling, researcher
at the Department of Medicine, Karolinska Institutet (Solna).

The study is largely based on CRISPR, CRISPR screening experiments on
isolated cells and analyses of the DepMap database.

The next step of the research is to understand how relevant the described mechanisms are.

"In cell cultures, we see a rapid and pronounced enrichment of cells with
p53 mutations when we subject the cells to CRISPR, provided, however, that cells with mutations are there from the start," says Dr. Wermeling. "So
we can show that the mechanism exists and factors that affect it, but
don't currently know at what level this is a genuine problem, and that's something we want to explore further in more clinic-centered tests."
The study was conducted in collaboration with David P. Lane's group
(MTC) and financed by the Swedish Research Council, the Swedish Cancer
Society, Karolinska Institutet, the Magnus Bergvall Foundation, the China Scholarship Council and the Nanyang Technological University-Karolinska Institutet Joint PhD Program (VSI).

========================================================================== Story Source: Materials provided by Karolinska_Institutet. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. Long Jiang, Katrine Ingelshed, Yunbing Shen, Sanjaykumar V Boddul,
Vaishnavi Srinivasan Iyer, Zsolt Kasza, Saikiran Sedimbi, David P
Lane, Fredrik Wermeling. CRISPR/Cas9-induced DNA damage enriches
for mutations in a p53-linked interactome: implications for
CRISPR-based therapies..

Cancer Research, 2021; canres.1692.2021 DOI:
10.1158/0008-5472.CAN-21- 1692 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/11/211118061556.htm

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