New insights into the link between CRISPR and mutant cells

When a gene is edited with CRISPR, a protein that protects cells from DNA damage p53 is activated. Therefore, cells that have mutations in p53 have a survival advantage, which could cause cancer. Researchers from Sweden’s Karolinska Institutet discovered new links between CRISPR and p53. This could help prevent the accumulation or mutated cells, without compromising the gene scissors effectiveness. The study published in Cancer Research, could be a key element in the future of precision medicine.

Many are optimistic about the possibilities for gene editing using CRISPR (gene-scissor) as one of the key components of the future’s precision medicine. There are many hurdles to be overcome before this method can become routine in hospitals.

One of these issues is the way cells react to DNA damage. CRISPR gene editing allows for controlled cell behavior. Cell damage activates the protein “first aid” response of the cell in response to DNA damage.

It is well-known that this method is less effective when p53 is active. However, cells can grow uncontrollably and develop cancerous cells if p53 not present. Over half of all cancers have a mutation of the gene for p53, which makes it ineffective to protect against uncontrolled cell growth. It is crucial to avoid the growth (enrichment) of these cells with mutations.

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

Researchers also discovered a network linking genes with mutations that have the same effect as the p53 mutations. They have shown that the transient inhibition of protein 53 may be a possible method to prevent enrichment cells with such mutations.

It could seem contradictory to expect the p53 receptor to be blocked in the CRISPR environment. Some research supports the idea that CRISPR can be made more effective by inhibiting p53. In our study, we have shown that this may also counteract the increase in cells that have mutations in p53 as well as a group of associated genes.”

Long Jiang, the study’s first author and doctoral student at Karolinska Institutet, Solna

CRISPR research is an important factor in the future clinical implementation. The network of candidate genes has been identified and must be closely monitored for any mutations that occur during CRISPR. One possible conclusion is that transient inhibition of the p53 protein could be a way to reduce the amount of mutant cells that are enriched.

Researchers also studied the DNA-damage response to determine if it could be used as a marker for the development more precise guideRNA sequences. These sequences are used to tell CRISPR which DNA sequence is to change.

Fredrik Wermeling (researcher at the Karolinska Institutet, Solna) stated that “We believe that the up-regulation of genes implicated in the DNA damage reaction could be a reliable indicator of the amount of unspecific or ‘off-targetactivity a guideRNA is experiencing and therefore aid in the selection of guideRNAs.”

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

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

Dr. Wermeling says, “In cell culture, we see an immediate and significant increase in cells with p53 mutants when we subject them to CRISPR,” provided that the cells that have mutations were present from the beginning.” “So we can prove that the mechanism is there and that various factors can affect it but we don’t know at what level it is an issue. That’s something that we want to explore through more clinic-based 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).

Journal reference:

Jiang, L., , et al. (2021). CRISPR/Cas9-induced DNA damages enriches mutations in an interactome p53-linked: Implications for CRISPR-based treatments. Cancer Research.

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Gemma Wilson

Gemma is a journalism graduate with keen interest in covering business news – specifically startups. She has as a keen eye for technologies and has predicted quite a few successful startups over the last couple of years.

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