Recombination may cause genotoxicity

Bohin, N., Carlson, E. A. & Samuelson, L. C. Stem Cell Rep. https://doi.org/10.1016/j.stemcr.2018.10.014 (2018).

The Cre–loxP recombination system is popular in in vivo genetic studies because its expression can be induced temporally in a cell-specific manner. Researchers have applied inducible Cre drivers in intestinal stem cells (ISCs) to manipulate genetic recombination and study ISC function. Bohin et al. report that intestine-specific CreER^T2 drivers, but not tamoxifen toxicity, can induce undesired DNA-cleavage events at cryptic loxP (cloxP) sites, which leads to reduced ISC function. Examining the Villin-CreER^T2 mouse strain, they observed that tamoxifen (TX)-activated CreER^T2 results in delayed crypt regeneration after epithelial cell damage induced by irradiation. They suggest that TX-activated CreER^T2 introduces cleavage at cloxP sites and DNA double-stranded breaks. They also observed that genotoxicity reduces organoid-forming efficiency and impairs the function of crypt base columnar stem cells. Therefore, they advise that future CreER mouse studies should include control samples for Cre-introduced genotoxicity.