Editors' ChoiceGENE THERAPY

CRISPR, cancer, and p53

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Sci. Signal.  17 Jul 2018:
Vol. 11, Issue 539, eaau7344
DOI: 10.1126/scisignal.aau7344

CRISPR-Cas9 genome editing is most efficient in cells lacking functional p53 protein, a phenotype common to cancer cells.

CRISPR-Cas9 technology has gained wide appeal for its potential to advance gene editing, to both study and cure disease. But just as the first human trials are set to begin, reports have emerged associating the technology with a cancer risk. Two studies published in Nature Medicine now show why. To replace a mutant gene, for example, CRISPR-Cas9 targets and excises the mutant gene, generating DNA strand breaks that are then repaired through recombination with synthetic, donor template DNA. However, cells have inherent mechanisms that respond quickly to this type of DNA damage, and the transcription factor p53 is at the center of these mechanisms. Haapaniemi et al. and Ihry et al. (see coverage by Urnov) showed that p53 antagonizes the efficiency of Cas9-mediated gene editing in target cells. CRISPR-Cas9 editing worked best in p53-deficient cell lines and subpopulations; in immortalized human retinal pigment epithelial (hRPE) cells and human pluripotent stem cells (hPSCs), deleting or reducing p53 increased the number of surviving cells with an edited genome. This technology therefore selects for p53-deficient cells, meaning that edited cells are vulnerable to mutagenesis and a gain in otherwise p53-antagonized signaling pathways that could result in tumors. In the Archives of Science Signaling, Stewart-Ornstein and Lahav show that p53 activity is dynamic and controlled by the kinase ATM. It is intriguing to wonder whether CRISPR-Cas9 could be either strategically timed to exploit the dips in p53 activity or combined with targeted, reversible inhibitors of ATM to only temporarily induce p53 deficiency. Together, these studies raise various considerations for both the procedure and the application of the CRISPR-Cas9 technology, but there may also be an interesting opportunity. The gene encoding p53 is mutated in many cancer types, and restoring p53 function is a (so-far elusive) goal in cancer therapy. But in an opinion piece published in Trends in Biotechnology, Chira et al. makes a case for using CRISPR-Cas9 gene editing technology to restore p53 in cells. Given that the technique relies on an inherent p53 deficiency, this may be a real possibility.

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