Abstract
The TP53 gene encodes the transcription factor and oncosuppressor p53 protein that regulates a multitude of intracellular metabolic pathways involved in DNA damage repair, cell cycle arrest, apoptosis, and senescence. In many cases, alterations (e.g., mutations of the TP53 gene) negatively affect these pathways resulting in tumor development. Recent advances in genome manipulation technologies, CRISPR/Cas9, in particular, brought us closer to therapeutic gene editing for the treatment of cancer and hereditary diseases. Genome-editing therapies for blood disorders, blindness, and cancer are currently being evaluated in clinical trials. Eventually CRISPR/Cas9 technology is expected to target TP53 as the most mutated gene in all types of cancers. A majority of TP53 mutations are missense which brings immense opportunities for the CRISPR/Cas9 system that has been successfully used for correcting single nucleotides in various models, both in vitro and in vivo. In this review, we highlight the recent clinical applications of CRISPR/Cas9 technology for therapeutic genome editing and discuss its perspectives for editing TP53 and regulating transcription of p53 pathway genes.
Highlights
The TP53 gene encodes the p53 protein, a well-known tumour suppressor involved in various regulatory pathways including cell cycle arrest, apoptosis, senescence and DNA repair
Cases, only one nucleotide is mutated inTP53 the TP53 gene leading to a single amino acid substitution in only one nucleotide is mutated in the gene leading to a single amino acid substitution in the Alterations in the TP53 gene are commonly associated with increased risk of cancer
In contrast to non-homologous end joining (NHEJ), the homology-directed repair (HDR) mechanism is generally less efficient, because it requires cell division, presence of homology sequence template prior ligation and can vary significantly depending on the cell type and state, genomic locus, and repair template. Both repair mechanisms are differentially regulated according to the phase of cell cycle, e.g., HDR is limited to S/G2, while NHEJ is functional throughout the entire cell cycle [35]
Summary
The TP53 gene encodes the p53 protein, a well-known tumour suppressor involved in various regulatory pathways including cell cycle arrest, apoptosis, senescence and DNA repair. The TP53 is the most frequently mutated gene in human cancer with mutations found in about half of all cancer cases. Neoplasia Information Exchange) project by AACR (American Association for Cancer Research). Alterations ininthe gene areare commonly associated with increased riskrisk of cancer. Cases, only one nucleotide is mutated inTP53 the TP53 gene leading to a single amino acid substitution in only one nucleotide is mutated in the gene leading to a single amino acid substitution in the Alterations in the TP53 gene are commonly associated with increased risk of cancer. The most frequent mutations areTP53 represented by G:C>A:T conversions cases, only one nucleotide is mutated in the gene leading to a single or amino acid substitution in that thatthe together amount for over half of TP53 somatic mutations in human cancers Types andand distribution of of nucleotide that result resultininsomatic somaticmutations mutations in
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