Exploration of genetic basis underlying individual differences in radiosensitivity within human populations using genome editing technology.

DNA double-strand breaks (DSBs) induced by ionizing radiation (IR) are the initial and critical step in major alteration of genetic information and cell death. To prevent deleterious effects, DNA repair systems recognize and re-join DNA DSBs in human cells. It has been suggested that there are individual differences in radiosensitivity within human populations, and that variations in DNA repair genes might contribute to this heterogeneity. Because confounding factors, including age, gender, smoking, and diverse genetic backgrounds within human populations, also influence the cellular radiosensitivity, to accurately measure the effect of candidate genetic variations on radiosensitivity, it is necessary to use human cultured cells with a uniform genetic background. However, a reverse genetics approach in human cultured cells is difficult because of their low level of homologous recombination. Engineered endonucleases used in genome editing technology, however, can enable the local activation of DNA repair pathways at the human genome target site to efficiently introduce genetic variations of interest into human cultured cells. Recently, we used this technology to demonstrate that heterozygous mutations of the ATM gene, which is responsible for a hyper-radiosensitive genetic disorder, ataxia-telangiectasia, increased the number of chromosomal aberrations after IR. Thus, understanding the heterozygous mutations of radiosensitive disorders should shed light on the genetic basis underlying individual differences in radiosensitivity within human populations.